1
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Yang H, Xia Y, Ma Y, Gao M, Hou S, Xu S, Wang Y. Inhibition of the cGAS-STING pathway: contributing to the treatment of cerebral ischemia-reperfusion injury. Neural Regen Res 2025; 20:1900-1918. [PMID: 38993125 PMCID: PMC11691458 DOI: 10.4103/nrr.nrr-d-24-00015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 03/05/2024] [Accepted: 05/02/2024] [Indexed: 07/13/2024] Open
Abstract
The cGAS-STING pathway plays an important role in ischemia-reperfusion injury in the heart, liver, brain, and kidney, but its role and mechanisms in cerebral ischemia-reperfusion injury have not been systematically reviewed. Here, we outline the components of the cGAS-STING pathway and then analyze its role in autophagy, ferroptosis, cellular pyroptosis, disequilibrium of calcium homeostasis, inflammatory responses, disruption of the blood-brain barrier, microglia transformation, and complement system activation following cerebral ischemia-reperfusion injury. We further analyze the value of cGAS-STING pathway inhibitors in the treatment of cerebral ischemia-reperfusion injury and conclude that the pathway can regulate cerebral ischemia-reperfusion injury through multiple mechanisms. Inhibition of the cGAS-STING pathway may be helpful in the treatment of cerebral ischemia-reperfusion injury.
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Affiliation(s)
- Hang Yang
- School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong Province, China
| | - Yulei Xia
- School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong Province, China
| | - Yue Ma
- School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong Province, China
| | - Mingtong Gao
- Department of Emergency, The Affiliated Hospital of Weifang Medical University, Weifang, Shandong Province, China
| | - Shuai Hou
- School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong Province, China
| | - Shanshan Xu
- Department of Emergency, The Affiliated Hospital of Weifang Medical University, Weifang, Shandong Province, China
| | - Yanqiang Wang
- Department of Neurology II, The Affiliated Hospital of Weifang Medical University, Weifang, Shandong Province, China
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2
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Cao L, Chang MX. Zebrafish CD44a variants suppress antiviral immunity through regulation of RIG-I ubiquitination and degradation. FISH & SHELLFISH IMMUNOLOGY 2025:110442. [PMID: 40412572 DOI: 10.1016/j.fsi.2025.110442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/26/2025] [Revised: 05/21/2025] [Accepted: 05/22/2025] [Indexed: 05/27/2025]
Abstract
Viral infections represent a major threat to host survival, with type I interferon (IFN-I) signaling serving as a central antiviral defense mechanism. The RIG-I-like receptor RIG-I detects viral RNA to initiate IFN-I production, yet the post-translational mechanisms regulating its activity remain poorly understood in teleost. While zebrafish CD44a, a cell adhesion molecule, protects against bacterial infections, its role in viral immunity-specifically in modulating RIG-I-mediated IFN-I signaling-has not yet been elucidated. This study characterizes the functions of zebrafish CD44a splice variants (CD44a_tv1 and CD44a_tv2) during Spring viremia of carp virus (SVCV) infection. Ectopic expression of CD44a variants enhanced viral replication and larval mortality, whereas CD44a deficiency reduced viral load and improved survival. Mechanistically, CD44a variants promoted K48-linked polyubiquitination and proteasomal degradation of RIG-I while inhibiting K63-linked activation-related ubiquitination, disrupting RLR pathway activation. Direct physical interaction between CD44a variants and RIG-I was confirmed via co-immunoprecipitation and confocal microscopy, demonstrating CD44a variants directly bind to RIG-I to facilitate RIG-I degradation and suppress IFN-I responses. These findings reveal a novel role for CD44a in antiviral immunity through dual regulation of RIG-I ubiquitination, highlighting its context-dependent duality-protecting against bacteria but exacerbating viral pathogenesis. Inhibiting the pro-viral pathogenic activity of CD44a while preserving or augmenting its anti-bacterial protective function thereby establishes promising strategies for targeted therapies against pathogen-specific infectious diseases.
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Affiliation(s)
- Lu Cao
- State Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture (CAS), State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, Hubei Province, 430072, China; School of Basic Medical Sciences, Hubei University of Chinese Medicine, Wuhan 430065, PR China; Hubei Shizhen Laboratory, Wuhan 430065, PR. China
| | - Ming Xian Chang
- State Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture (CAS), State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, Hubei Province, 430072, China; University of Chinese Academy of Sciences, Beijing 100049, China.
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3
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Nehar-Belaid D, Mejías A, Xu Z, Marches R, Yerrabelli R, Chen G, Mertz S, Ye F, Sánchez PJ, Tsang JS, Aydillo T, Miorin L, Cupic A, García-Sastre A, Ucar D, Banchereau JF, Pascual V, Ramilo O. SARS-CoV-2 induced immune perturbations in infants vary with disease severity and differ from adults' responses. Nat Commun 2025; 16:4562. [PMID: 40379618 PMCID: PMC12084365 DOI: 10.1038/s41467-025-59411-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Accepted: 04/22/2025] [Indexed: 05/19/2025] Open
Abstract
Differences in immune profiles of children and adults with COVID-19 have been previously described. However, no systematic studies have been reported from infants hospitalized with severe disease. We applied a multidimensional approach to decipher the immune responses of SARS-CoV-2 infected infants (n = 26; 10 subacute, 11 moderate and 5 severe disease; median age = 1.6 months) and matched controls (n = 14; median age = 2 months). Single cell (scRNA-seq) profiling of PBMCs revealed substantial alterations in cell composition in SARS-CoV-2 infected infants; with most cell-types switching to an interferon-stimulated gene (ISGhi) state including: (i) CD14+ monocytes co-expressing ISGs and inflammasome-related molecules, (ii) ISGhi naive CD4+ T cells, (iii) ISGhi proliferating cytotoxic CD8+ T cells, and (iv) ISGhi naive and transitional B cells. We observe increased serum concentrations of both interferons and inflammatory cytokines in infected infants. Antibody responses to SARS-CoV-2 are also consistently detected in the absence of anti-IFN autoantibodies. Compared with infected adults, infants display a similar ISG signature in monocytes but a markedly enhanced ISG signature in T and B cells. These findings provide insights into the distinct immune responses to SARS-CoV-2 in the first year of life and underscore the importance of further defining the unique features of early life immunity.
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Affiliation(s)
| | - Asunción Mejías
- Department of Pediatrics, Nationwide Children's Hospital and The Ohio State University College of Medicine, Columbus, OH, USA
- Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, 43205, USA
- Department of Infectious Diseases, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Zhaohui Xu
- Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, 43205, USA
- Department of Infectious Diseases, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Radu Marches
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, 06032, USA
| | - Rushil Yerrabelli
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, 06032, USA
| | - Guo Chen
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, 06032, USA
| | - Sara Mertz
- Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, 43205, USA
| | - Fang Ye
- Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, 43205, USA
| | - Pablo J Sánchez
- Department of Pediatrics, Division of Neonatology and Center for Perinatal Research, Ohio Perinatal Research Network, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, USA
| | - John S Tsang
- Center for Systems and Engineering Immunology, Departments of Immunobiology and Biomedical Engineering, Yale University, New Haven, CT, 06520, USA
- Department of Biomedical Engineering, Yale University, New Haven, CT, USA
- Chan Zuckerberg Biohub NY, New Haven, CT, USA
| | - Teresa Aydillo
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA
- Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA
| | - Lisa Miorin
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA
- Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA
| | - Anastasija Cupic
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA
- Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA
| | - Adolfo García-Sastre
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA
- Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA
- Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA
- Department of Pathology, Molecular and Cell-Based Medicine, One Gustave L. Levy Place, New York, NY, 10029, USA
- Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA
| | - Duygu Ucar
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, 06032, USA
| | - Jacques F Banchereau
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, 06032, USA.
- Immunoledge LLC, Montclair, NJ, USA.
| | - Virginia Pascual
- Drukier Institute for Children's Health and Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA.
| | - Octavio Ramilo
- Department of Pediatrics, Nationwide Children's Hospital and The Ohio State University College of Medicine, Columbus, OH, USA.
- Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, 43205, USA.
- Department of Infectious Diseases, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
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4
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Ramalho T, Gazzinelli RT. Itaconate boosts type I IFN response by disrupting cytoprotection. Nat Metab 2025:10.1038/s42255-025-01274-1. [PMID: 40251411 DOI: 10.1038/s42255-025-01274-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/20/2025]
Affiliation(s)
- Theresa Ramalho
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA.
| | - Ricardo Tostes Gazzinelli
- Department of Medicine, Division of Infectious Disease and Immunology, University of Massachusetts Chan Medical School, Worcester, MA, USA.
- Centro de Tecnologia de Vacinas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
- Instituto René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Brazil.
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Hos NJ, Fischer J, Murthy AMV, Hejazi Z, Krönke M, Hos D, Robinson N. P62 inhibits IL-1β release during Salmonella Typhimurium infection of macrophages. Front Cell Infect Microbiol 2025; 15:1495567. [PMID: 40276384 PMCID: PMC12018378 DOI: 10.3389/fcimb.2025.1495567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Accepted: 03/14/2025] [Indexed: 04/26/2025] Open
Abstract
Macrophages are critical for the innate immune defense against the facultative intracellular Gram-negative bacterium Salmo\nella enterica serovar Typhimurium. Following phagocytosis by macrophages, S. Typhimurium activates cytoplasmic NLRC3 and NLRP4 inflammasomes, which share the adaptor ASC, resulting in the secretion of the pro-inflammatory cytokine IL-1β. To prevent excessive inflammation and tissue damage, inflammatory signaling pathways are tightly controlled. Recently, autophagy has been suggested to limit inflammation by targeting activated inflammasomes for autophagic degradation. However, the importance of the autophagic adaptor Sequestome-1 (hereafter, p62) for regulating inflammasome activation remains poorly understood. We report here that p62 restricts inflammasome availability and subsequent IL-1β secretion in macrophages infected with S. Typhimurium by targeting the inflammasome adaptor ASC for autophagic degradation. Importantly, loss of p62 resulted in impaired autophagy and increased IL-1β secretion, as well as IL-10 and IFN-β release. In summary, our results demonstrate a novel role for p62 in inducing autophagy and balancing major pro- and anti-inflammatory signaling pathways to prevent excessive inflammation during S. Typhimurium infection of macrophages.
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Affiliation(s)
- Nina Judith Hos
- Institute for Medical Microbiology, Immunology and Hygiene, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
- Cluster of Excellence in Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
- German Center for Infection Research (DZIF), Partner Site Bonn-Cologne, Cologne, Germany
| | - Julia Fischer
- Cluster of Excellence in Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
- German Center for Infection Research (DZIF), Partner Site Bonn-Cologne, Cologne, Germany
- Department I of Internal Medicine, Division of Infectious Diseases, University of Cologne, Cologne, Germany
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
- Department B of Internal Medicine, University of Münster, University Hospital of Münster, Münster, Germany
| | - Ambika M. V. Murthy
- Center for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia
- Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA, Australia
| | - Zahra Hejazi
- German Center for Infection Research (DZIF), Partner Site Bonn-Cologne, Cologne, Germany
- Department I of Internal Medicine, Division of Infectious Diseases, University of Cologne, Cologne, Germany
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
| | - Martin Krönke
- Institute for Medical Microbiology, Immunology and Hygiene, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
- Cluster of Excellence in Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
- German Center for Infection Research (DZIF), Partner Site Bonn-Cologne, Cologne, Germany
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
| | - Deniz Hos
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Nirmal Robinson
- Institute for Medical Microbiology, Immunology and Hygiene, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
- Cluster of Excellence in Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
- Center for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA, Australia
- Adelaide Medical School, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA, Australia
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6
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Singh V, Ubaid S, Kashif M, Singh T, Singh G, Pahwa R, Singh A. Role of inflammasomes in cancer immunity: mechanisms and therapeutic potential. J Exp Clin Cancer Res 2025; 44:109. [PMID: 40155968 PMCID: PMC11954315 DOI: 10.1186/s13046-025-03366-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Accepted: 03/15/2025] [Indexed: 04/01/2025] Open
Abstract
Inflammasomes are multi-protein complexes that detect pathogenic and damage-associated molecular patterns, activating caspase-1, pyroptosis, and the maturation of pro-inflammatory cytokines such as IL-1β and IL-18Within the tumor microenvironment, inflammasomes like NLRP3 play critical roles in cancer initiation, promotion, and progression. Their activation influences the crosstalk between innate and adaptive immunity by modulating immune cell recruitment, cytokine secretion, and T-cell differentiation. While inflammasomes can contribute to tumor growth and metastasis through chronic inflammation, their components also present novel therapeutic targets. Several inhibitors targeting inflammasome components- such as sensor proteins (e.g., NLRP3, AIM2), adaptor proteins (e.g., ASC), caspase-1, and downstream cytokines- are being explored to modulate inflammasome activity. These therapeutic strategies aim to modulate inflammasome activity to enhance anti-tumor immune responses and improve clinical outcomes. Understanding the role of inflammasomes in cancer immunity is crucial for developing interventions that effectively bridge innate and adaptive immune responses for better therapeutic outcomes.
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Affiliation(s)
- Vivek Singh
- Thoracic Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Saba Ubaid
- Department of Biochemistry, King George'S Medical University (KGMU), U.P, Lucknow, 226003, India
| | - Mohammad Kashif
- Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA
| | - Tanvi Singh
- Department of Biochemistry, King George'S Medical University (KGMU), U.P, Lucknow, 226003, India
| | - Gaurav Singh
- Department of Biochemistry, King George'S Medical University (KGMU), U.P, Lucknow, 226003, India
| | - Roma Pahwa
- Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Anand Singh
- Thoracic Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
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7
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Mao H, Guo F, Wang C, Jiang K, Li H, Lei L. ACLY inhibitor reduced Porphyromonas gingivalis-induced pyroptosis by suppressing microtubules acetylation in macrophages. Int Immunopharmacol 2025; 150:114249. [PMID: 39955916 DOI: 10.1016/j.intimp.2025.114249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 02/04/2025] [Accepted: 02/05/2025] [Indexed: 02/18/2025]
Abstract
OBJECTIVES This study aimed to investigate the effect of acetylation of α-tubulin induced by ATP-citrate lyase (ACLY) activation on pyroptosis process in mouse bone marrow derived macrophages (BMDMs). MATERIALS AND METHODS Level of phospho-ACLY was assessed in normal and inflamed gingiva. Mouse BMDMs were harvested and infected with Porphyromonas gingivalis. The mRNA and protein levels of genes were analyzed by real-time quantitative PCR and western blotting, respectively. Polymerization and acetylation of microtubules were detected with immunofluorescence. Lactate dehydrogenase (LDH) activity assay, immunofluorescence, and ELISA were performed to determine pyroptosis in P.gingivalis-induced BMDMs. RESULTS Elevated expression of phospho-ACLY was observed in the inflamed gingiva. P. gingivalis infection was shown to promote pyroptosis in mouse BMDMs. Moreover, P. gingivalis-induced BMDMs showed increased phospho-ACLY, as well as polymerization and acetylation of microtubules. Inhibition and knockdown of ACLY showed depolymerization and decreased acetylation of microtubules, thus resulting in reduced P. gingivalis-induced pyroptosis in BMDMs. CONCLUSIONS Our findings suggest that ACLY-mediated dynamics of microtubules participate in the progress of periodontitis. P. gingvalis-triggered phospho-ACLY target the microtubule cytoskeleton by influencing acetylation of tubulin, facilitating NLRP3 inflammasome activation and pyroptosis.
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Affiliation(s)
- Huimin Mao
- Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University, Nanjing, China; Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University, Nanjing, China.
| | - Feng Guo
- Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University, Nanjing, China; Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University, Nanjing, China.
| | - Chenxu Wang
- Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University, Nanjing, China; Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University, Nanjing, China.
| | - Ke Jiang
- Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University, Nanjing, China; Central Laboratory of Stomatology, Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University, Nanjing, China.
| | - Houxuan Li
- Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University, Nanjing, China.
| | - Lang Lei
- Nanjing Stomatological Hospital, Affiliated Hospital of Medical School, Institute of Stomatology, Nanjing University, Nanjing, China.
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8
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Fahey DL, Patel N, Watford WT. TPL2 kinase activity is required for Il1b transcription during LPS priming but dispensable for NLRP3 inflammasome activation. Front Immunol 2025; 16:1496613. [PMID: 40170849 PMCID: PMC11958189 DOI: 10.3389/fimmu.2025.1496613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2024] [Accepted: 02/19/2025] [Indexed: 04/03/2025] Open
Abstract
The NLRP3 inflammasome complex is an important mechanism for regulating the release of pro-inflammatory cytokines, IL-1β and IL-18, in response to harmful pathogens. Overproduction of pro-inflammatory cytokines has been linked to cryopyrin-associated periodic syndrome, arthritis, and other inflammatory conditions. It has been previously shown that tumor progression locus 2, a serine-threonine kinase, promotes IL-1β synthesis in response to LPS stimulation; however, whether TPL2 kinase activity is required during inflammasome priming to promote Il1b mRNA transcription and/or during inflammasome activation for IL-1β secretion remained unknown. In addition, whether elevated type I interferons, a consequence of either Tpl2 genetic ablation or inhibition of TPL2 kinase activity, decreases IL-1β expression or inflammasome function has not been explored. Using LPS-stimulated primary murine bone marrow-derived macrophages, we determined that TPL2 kinase activity is required for transcription of Il1b, but not Nlrp3, Il18, caspase-1 (Casp1), or gasdermin-D (Gsdmd) during inflammasome priming. Both Casp1 and Gsdmd mRNA synthesis decreased in the absence of type I interferon signaling, evidence of crosstalk between type I interferons and the inflammasome. Our results demonstrate that TPL2 kinase activity is differentially required for the expression of inflammasome precursor cytokines and components but is dispensable for inflammasome activation. These data provide the foundation for the further exploration of TPL2 kinase inhibitor as a potential therapeutic in inflammatory diseases.
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Affiliation(s)
- Denise L. Fahey
- Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA, United States
| | - Niki Patel
- College of Veterinary Medicine, University of Georgia, Athens, GA, United States
| | - Wendy T. Watford
- Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA, United States
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9
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Fekete R, Simats A, Bíró E, Pósfai B, Cserép C, Schwarcz AD, Szabadits E, Környei Z, Tóth K, Fichó E, Szalma J, Vida S, Kellermayer A, Dávid C, Acsády L, Kontra L, Silvestre-Roig C, Moldvay J, Fillinger J, Csikász-Nagy A, Hortobágyi T, Liesz A, Benkő S, Dénes Á. Microglia dysfunction, neurovascular inflammation and focal neuropathologies are linked to IL-1- and IL-6-related systemic inflammation in COVID-19. Nat Neurosci 2025; 28:558-576. [PMID: 40050441 PMCID: PMC11893456 DOI: 10.1038/s41593-025-01871-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Accepted: 12/17/2024] [Indexed: 03/12/2025]
Abstract
COVID-19 is associated with diverse neurological abnormalities, but the underlying mechanisms are unclear. We hypothesized that microglia, the resident immune cells of the brain, are centrally involved in this process. To study this, we developed an autopsy platform allowing the integration of molecular anatomy, protein and mRNA datasets in postmortem mirror blocks of brain and peripheral organ samples from cases of COVID-19. We observed focal loss of microglial P2Y12R, CX3CR1-CX3CL1 axis deficits and metabolic failure at sites of virus-associated vascular inflammation in severely affected medullary autonomic nuclei and other brain areas. Microglial dysfunction is linked to mitochondrial injury at sites of excessive synapse and myelin phagocytosis and loss of glutamatergic terminals, in line with proteomic changes of synapse assembly, metabolism and neuronal injury. Furthermore, regionally heterogeneous microglial changes are associated with viral load and central and systemic inflammation related to interleukin (IL)-1 or IL-6 via virus-sensing pattern recognition receptors and inflammasomes. Thus, SARS-CoV-2-induced inflammation might lead to a primarily gliovascular failure in the brain, which could be a common contributor to diverse COVID-19-related neuropathologies.
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Affiliation(s)
- Rebeka Fekete
- Momentum Laboratory of Neuroimmunology, HUN-REN Institute of Experimental Medicine, Budapest, Hungary
| | - Alba Simats
- Institute for Stroke and Dementia Research, LMU University Hospital, LMU Munich, Munich, Germany
| | - Eduárd Bíró
- Laboratory of Inflammation-Physiology, Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Balázs Pósfai
- Momentum Laboratory of Neuroimmunology, HUN-REN Institute of Experimental Medicine, Budapest, Hungary
| | - Csaba Cserép
- Momentum Laboratory of Neuroimmunology, HUN-REN Institute of Experimental Medicine, Budapest, Hungary
| | - Anett D Schwarcz
- Momentum Laboratory of Neuroimmunology, HUN-REN Institute of Experimental Medicine, Budapest, Hungary
- János Szentágothai Doctoral School of Neuroscience, Semmelweis University, Budapest, Hungary
| | - Eszter Szabadits
- Momentum Laboratory of Neuroimmunology, HUN-REN Institute of Experimental Medicine, Budapest, Hungary
| | - Zsuzsanna Környei
- Momentum Laboratory of Neuroimmunology, HUN-REN Institute of Experimental Medicine, Budapest, Hungary
| | - Krisztina Tóth
- Momentum Laboratory of Neuroimmunology, HUN-REN Institute of Experimental Medicine, Budapest, Hungary
| | | | - János Szalma
- Cytocast Hungary Kft, Budapest, Hungary
- Pázmány Péter Catholic University, Faculty of Information Technology and Bionics, Budapest, Hungary
| | - Sára Vida
- Momentum Laboratory of Neuroimmunology, HUN-REN Institute of Experimental Medicine, Budapest, Hungary
| | - Anna Kellermayer
- Momentum Laboratory of Neuroimmunology, HUN-REN Institute of Experimental Medicine, Budapest, Hungary
- János Szentágothai Doctoral School of Neuroscience, Semmelweis University, Budapest, Hungary
| | - Csaba Dávid
- Department of Anatomy, Histology and Embryology, Semmelweis University, Budapest, Hungary
- Lendület Laboratory of Thalamus Research, HUN-REN Institute of Experimental Medicine, Budapest, Hungary
| | - László Acsády
- Lendület Laboratory of Thalamus Research, HUN-REN Institute of Experimental Medicine, Budapest, Hungary
| | - Levente Kontra
- Bioinformatics Unit, HUN-REN Institute of Experimental Medicine, Budapest, Hungary
| | - Carlos Silvestre-Roig
- Institute for Experimental Pathology (ExPat), Center for Molecular Biology of Inflammation, WWU Muenster, Muenster, Germany
| | - Judit Moldvay
- I. Department of Pulmonology, National Korányi Institute of Pulmonology, Budapest, Hungary
- Pulmonology Clinic, Szeged University, Albert Szent-Gyorgyi Medical School, Szeged, Hungary
| | - János Fillinger
- Department of Pathology, National Korányi Institute of Pulmonology, Budapest, Hungary
| | - Attila Csikász-Nagy
- Cytocast Hungary Kft, Budapest, Hungary
- Pázmány Péter Catholic University, Faculty of Information Technology and Bionics, Budapest, Hungary
| | - Tibor Hortobágyi
- Institute of Pathology, Faculty of Medicine, University of Szeged, Szeged, Hungary
- Department of Neurology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- Institute of Neuropathology, Universitätsspital Zürich, Zurich, Switzerland
| | - Arthur Liesz
- Institute for Stroke and Dementia Research, LMU University Hospital, LMU Munich, Munich, Germany
- Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
| | - Szilvia Benkő
- Laboratory of Inflammation-Physiology, Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Ádám Dénes
- Momentum Laboratory of Neuroimmunology, HUN-REN Institute of Experimental Medicine, Budapest, Hungary.
- Mercator Fellow, Institute for Stroke and Dementia Research, LMU University Hospital, LMU Munich, Munich, Germany.
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10
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Suresh Kumar Meena Kumari M, Liu P, Nitchman MS, Chaudhary S, Jump K, Morales Y, Miller EA, Shecter I, Stadecker MJ, Kalantari P. NLRP3 and AIM2 inflammasomes exacerbate the pathogenic Th17 cell response to eggs of the helminth Schistosoma mansoni. PLoS Pathog 2025; 21:e1012108. [PMID: 40100932 PMCID: PMC11918320 DOI: 10.1371/journal.ppat.1012108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Accepted: 02/09/2025] [Indexed: 03/20/2025] Open
Abstract
Infection with the helminth Schistosoma mansoni can cause exacerbated morbidity and mortality via a pathogenic host CD4 T cell-mediated immune response directed against parasite egg antigens, with T helper (Th) 17 cells playing a major role in the development of severe granulomatous hepatic immunopathology. The role of inflammasomes in intensifying disease has been reported; however, neither the types of caspases and inflammasomes involved, nor their impact on the Th17 response are known. Here we show that enhanced egg-induced IL-1β secretion and pyroptotic cell death required both caspase-1 and caspase-8 as well as NLRP3 and AIM2 inflammasome activation. Schistosome genomic DNA activated AIM2, whereas reactive oxygen species, potassium efflux and cathepsin B, were the major activators of NLRP3. NLRP3 and AIM2 deficiency led to a significant reduction in pathogenic Th17 responses, suggesting their crucial and non-redundant role in promoting inflammation. Additionally, we show that NLRP3- and AIM2-induced IL-1β suppressed IL-4 and protective Type I IFN (IFN-I) production, which further enhanced inflammation. IFN-I signaling also curbed inflammasome- mediated IL-1β production suggesting that these two antagonistic pathways shape the severity of disease. Lastly, Gasdermin D (Gsdmd) deficiency resulted in a marked decrease in egg-induced granulomatous inflammation. Our findings establish NLRP3/AIM2-Gsdmd axis as a central inducer of pathogenic Th17 responses which is counteracted by IFN-I pathway in schistosomiasis.
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Affiliation(s)
- Madhusoodhanan Suresh Kumar Meena Kumari
- Department of Veterinary and Biomedical Sciences, Center for Molecular Immunology and Infectious Disease, Pennsylvania State University, University Park, Pennsylvania, United States of America
| | - Pengyu Liu
- Department of Veterinary and Biomedical Sciences, Center for Molecular Immunology and Infectious Disease, Pennsylvania State University, University Park, Pennsylvania, United States of America
| | - Megan S. Nitchman
- Department of Veterinary and Biomedical Sciences, Center for Molecular Immunology and Infectious Disease, Pennsylvania State University, University Park, Pennsylvania, United States of America
| | - Santoshi Chaudhary
- Department of Veterinary and Biomedical Sciences, Center for Molecular Immunology and Infectious Disease, Pennsylvania State University, University Park, Pennsylvania, United States of America
| | - Kaile Jump
- Department of Veterinary and Biomedical Sciences, Center for Molecular Immunology and Infectious Disease, Pennsylvania State University, University Park, Pennsylvania, United States of America
| | - Yoelkys Morales
- Department of Immunology, Tufts University School of Medicine, Boston, Massachusetts, United States of America
| | - Emily A. Miller
- Department of Immunology, Tufts University School of Medicine, Boston, Massachusetts, United States of America
| | - Ilana Shecter
- Department of Immunology, Tufts University School of Medicine, Boston, Massachusetts, United States of America
| | - Miguel J. Stadecker
- Department of Immunology, Tufts University School of Medicine, Boston, Massachusetts, United States of America
| | - Parisa Kalantari
- Department of Veterinary and Biomedical Sciences, Center for Molecular Immunology and Infectious Disease, Pennsylvania State University, University Park, Pennsylvania, United States of America
- Department of Immunology, Tufts University School of Medicine, Boston, Massachusetts, United States of America
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11
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He KL, Yu X, Xia L, Xie YD, Qi EB, Wan L, Hua XM, Jing CH. A new perspective on the regulation of neuroinflammation in intracerebral hemorrhage: mechanisms of NLRP3 inflammasome activation and therapeutic strategies. Front Immunol 2025; 16:1526786. [PMID: 40083546 PMCID: PMC11903264 DOI: 10.3389/fimmu.2025.1526786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Accepted: 02/10/2025] [Indexed: 03/16/2025] Open
Abstract
Intracerebral hemorrhage (ICH), a specific subtype within the spectrum of stroke disorders, is characterized by its high mortality and significant risk of long-term disability. The initiation and progression of neuroinflammation play a central and critical role in the pathophysiology of ICH. The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, a protein complex involved in initiating inflammation, is the central focus of this article. Microglia and astrocytes play critical roles in the inflammatory damage process associated with neuroinflammation. The NLRP3 inflammasome is expressed within both types of glial cells, and its activation drives these cells toward a pro-inflammatory phenotype, which exacerbates inflammatory damage in the brain. However, the regulatory relationship between these two cell types remains to be explored. Targeting NLRP3 inflammasomes in microglia or astrocytes may provide an effective approach to mitigate neuroinflammation following ICH. This article first provides an overview of the composition and activation mechanisms of the NLRP3 inflammasome. Subsequently, it summarizes recent research findings on novel signaling pathways that regulate NLRP3 inflammasome activity. Finally, we reviewed recent progress in NLRP3 inflammasome inhibitors, highlighting the clinical translation potential of certain candidates. These inhibitors hold promise as innovative strategies for managing inflammation following ICH.
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Affiliation(s)
- Kai-long He
- Department of Neurosurgery, XinHua Hospital, Affiliated to Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Xian Yu
- Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Lei Xia
- Department of Neurosurgery, XinHua Hospital, Affiliated to Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Yan-dong Xie
- Department of Neurosurgery, XinHua Hospital, Affiliated to Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - En-bo Qi
- Department of Neurosurgery, XinHua Hospital, Affiliated to Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Liang Wan
- Department of Neurosurgery, XinHua Hospital, Affiliated to Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Xu-ming Hua
- Department of Neurosurgery, XinHua Hospital, Affiliated to Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Chao-hui Jing
- Department of Neurosurgery, XinHua Hospital, Affiliated to Shanghai JiaoTong University School of Medicine, Shanghai, China
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12
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Kawasaki H. A mechanistic review-regulation of silica-induced pulmonary inflammation by IL-10 and exacerbation by Type I IFN. Inhal Toxicol 2025; 37:59-73. [PMID: 39955624 DOI: 10.1080/08958378.2025.2465378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Accepted: 02/05/2025] [Indexed: 02/17/2025]
Abstract
Occupational exposure to crystalline silica (CS) is known to induce silicosis, a chronic lung disease characterized by the formation of granulomas and severe lung fibrosis. Specifically, individuals exposed to low doses of CS may develop silicosis after a decade or more of exposure. Similarly, in rat silicosis models exposed to occupationally relevant doses of α-quartz, there is an initial phase characterized by minimal and well-controlled pulmonary inflammation, followed by the development of robust and persistent inflammation. During the initial phase, the inflammation provoked by α-quartz is subdued by two mechanisms. Firstly, α-quartz particles are engulfed by alveolar macrophages (AMs) of the alternatively activated (M2) subtype and interstitial macrophages (IMs), limiting their interaction with other lung cells. Secondly, the anti-inflammatory cytokine, interleukin (IL)-10, is constitutively expressed by these macrophages, further dampening the inflammatory response. In the later inflammatory phase, IL-10-dependent anti-inflammatory state is disrupted by Type I interferons (IFNs), leading to the production of pro-inflammatory cytokines in response to α-quartz, aided by lipopolysaccharides (LPS). This review delves into the complex pathways involving IL-10, LPS, and Type I IFNs in α-quartz-induced pulmonary inflammation, offering a detailed analysis of the underlying mechanisms and identifying areas for future research.
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13
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Otálora-Alcaraz A, Reilly T, Oró-Nolla M, Sun MC, Costelloe L, Kearney H, Patra PH, Downer EJ. The NLRP3 inflammasome: A central player in multiple sclerosis. Biochem Pharmacol 2025; 232:116667. [PMID: 39647604 DOI: 10.1016/j.bcp.2024.116667] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Revised: 11/06/2024] [Accepted: 11/25/2024] [Indexed: 12/10/2024]
Abstract
Multiple sclerosis (MS) is a neurological autoimmune condition associated with many symptoms including spasticity, pain, limb numbness and weakness. It is characterised by inflammatory demyelination and axonal degeneration of the brain and spinal cord. A range of disease-modifying therapies (DMTs) are available to suppress inflammatory disease activity in MS, however, there is a pressing need for new therapeutic avenues as DMTs have a limited ability to suppress confirmed disability progression. A body of literature indicates that innate immune inflammation is linked to MS progression. The nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing protein 3 (NLRP3) inflammasome has a well-established function in innate immunity which is closely associated with the pathogenesis of neuroinflammatory conditions. Evidence suggests that the inflammasome may be a therapeutic target in disorders such as MS and at present, inhibitors of the NLRP3 inflammasome are in pre-clinical development. Therefore, this review systematically highlights the pathogenic role of inflammasomes in MS, presenting an overview of research evidence linking inflammasome-related polymorphisms to MS susceptibility, and gathering evidence investigating NLRP3 biomarkers in MS. The role of the NLRP3 inflammasome in murine models of MS is furthermore discussed. Finally, a significant component of this review focuses on evidence that NLRP3 signalling components are novel drug targets in MS. Overall this review defines the role of the inflammasome in MS pathogenesis and identifies inflammasome inhibitor targets that warrant full investigation in MS and related disorders.
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Affiliation(s)
- Almudena Otálora-Alcaraz
- Discipline of Physiology, School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
| | - Thomas Reilly
- Discipline of Physiology, School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
| | - Martí Oró-Nolla
- Discipline of Physiology, School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
| | - Melody Cui Sun
- Discipline of Physiology, School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
| | - Lisa Costelloe
- Department of Neurology, Beaumont Hospital, Dublin, Ireland
| | - Hugh Kearney
- MS Unit, Department of Neurology, St. James's Hospital, Dublin, Ireland; Academic Unit of Neurology, School of Medicine, Trinity College Dublin, Ireland
| | - Pabitra H Patra
- Transpharmation Ltd., London Biosciences Innovation Centre, London, United Kingdom
| | - Eric J Downer
- Discipline of Physiology, School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
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14
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Tork MAB, Fotouhi S, Roozi P, Negah SS. Targeting NLRP3 Inflammasomes: A Trojan Horse Strategy for Intervention in Neurological Disorders. Mol Neurobiol 2025; 62:1840-1881. [PMID: 39042218 DOI: 10.1007/s12035-024-04359-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Accepted: 07/09/2024] [Indexed: 07/24/2024]
Abstract
Recently, a growing focus has been on identifying critical mechanisms in neurological diseases that trigger a cascade of events, making it easier to target them effectively. One such mechanism is the inflammasome, an essential component of the immune response system that plays a crucial role in disease progression. The NLRP3 (nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain containing 3) inflammasome is a subcellular multiprotein complex that is widely expressed in the central nervous system (CNS) and can be activated by a variety of external and internal stimuli. When activated, the NLRP3 inflammasome triggers the production of proinflammatory cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18) and facilitates rapid cell death by assembling the inflammasome. These cytokines initiate inflammatory responses through various downstream signaling pathways, leading to damage to neurons. Therefore, the NLRP3 inflammasome is considered a significant contributor to the development of neuroinflammation. To counter the damage caused by NLRP3 inflammasome activation, researchers have investigated various interventions such as small molecules, antibodies, and cellular and gene therapy to regulate inflammasome activity. For instance, recent studies indicate that substances like micro-RNAs (e.g., miR-29c and mR-190) and drugs such as melatonin can reduce neuronal damage and suppress neuroinflammation through NLRP3. Furthermore, the transplantation of bone marrow mesenchymal stem cells resulted in a significant reduction in the levels of pyroptosis-related proteins NLRP3, caspase-1, IL-1β, and IL-18. However, it would benefit future research to have an in-depth review of the pharmacological and biological interventions targeting inflammasome activity. Therefore, our review of current evidence demonstrates that targeting NLRP3 inflammasomes could be a pivotal approach for intervention in neurological disorders.
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Affiliation(s)
- Mohammad Amin Bayat Tork
- Clinical Research Development Unit, Imam Reza Hospital, Mashhad University of Medical Sciences, Mashhad, Iran
- Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Soroush Fotouhi
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Parvin Roozi
- Department of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Sajad Sahab Negah
- Clinical Research Development Unit, Imam Reza Hospital, Mashhad University of Medical Sciences, Mashhad, Iran.
- Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
- Shefa Neuroscience Research Center, Khatam Alanbia Hospital, Tehran, Iran.
- Department of Neuroscience, Faculty of Medicine, Mashhad University of Medical Sciences, Pardis Campus, Azadi Square, Kalantari Blvd., Mashhad, Iran.
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15
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Benamar M, Lai PS, Huang CY, Chen Q, Oktelik FB, Contini P, Wang M, Okin D, Crestani E, Fong J, Fion TMC, Gokbak MN, Harb H, Phipatanakul W, Marri L, Vassallo C, Guastalla A, Kim M, Sui HY, Berra L, Goldberg MB, Angelini C, De Palma R, Chatila TA. Notch4 regulatory T cells and SARS-CoV-2 viremia shape COVID19 survival outcome. Allergy 2025; 80:557-569. [PMID: 39361431 PMCID: PMC11805648 DOI: 10.1111/all.16333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 08/05/2024] [Accepted: 09/07/2024] [Indexed: 10/05/2024]
Abstract
BACKGROUND Immune dysregulation and SARS-CoV-2 plasma viremia have been implicated in fatal COVID-19 disease. However, how these two factors interact to shape disease outcomes is unclear. METHODS We carried out viral and immunological phenotyping on a prospective cohort of 280 patients with COVID-19 presenting to acute care hospitals in Boston, Massachusetts and Genoa, Italy between June 1, 2020 and February 8, 2022. Disease severity, mortality, plasma viremia, and immune dysregulation were assessed. A mouse model of lethal H1N1 influenza infection was used to analyze the therapeutic potential of Notch4 and pyroptosis inhibition in disease outcome. RESULTS Stratifying patients based on %Notch4+ Treg cells and/or the presence of plasma viremia identified four subgroups with different clinical trajectories and immune phenotypes. Patients with both high %Notch4+ Treg cells and viremia suffered the most disease severity and 90-day mortality compared to the other groups even after adjusting for baseline comorbidities. Increased Notch4 and plasma viremia impacted different arms of the immune response in SARS-CoV-2 infection. Increased Notch4 was associated with decreased Treg cell amphiregulin expression and suppressive function whereas plasma viremia was associated with increased monocyte cell pyroptosis. Combinatorial therapies using Notch4 blockade and pyroptosis inhibition induced stepwise protection against mortality in a mouse model of lethal H1N1 influenza infection. CONCLUSIONS The clinical trajectory and survival outcome in hospitalized patients with COVID-19 is predicated on two cardinal factors in disease pathogenesis: viremia and Notch4+ Treg cells. Intervention strategies aimed at resetting the immune dysregulation in COVID-19 by antagonizing Notch4 and pyroptosis may be effective in severe cases of viral lung infection.
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Affiliation(s)
- Mehdi Benamar
- Division of Immunology, Boston Children’s Hospital, Boston, Massachusetts, USA
- Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA
| | - Peggy S. Lai
- Division of Pulmonary and Critical Care, Massachusetts General Hospital, Boston, Massachusetts, USA
- Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
| | - Ching-Ying Huang
- Division of Pulmonary and Critical Care, Massachusetts General Hospital, Boston, Massachusetts, USA
- Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
| | - Qian Chen
- Division of Immunology, Boston Children’s Hospital, Boston, Massachusetts, USA
- Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA
| | - Fatma Betul Oktelik
- Division of Immunology, Boston Children’s Hospital, Boston, Massachusetts, USA
- Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA
| | - Paola Contini
- Department of Internal Medicine, Unit of Clinical Immunology and Translational Medicine, University of Genova, Italy
- Clinical Immunology Division, IRCCS-San Martino Hospital-Genova
| | - Muyun Wang
- Division of Immunology, Boston Children’s Hospital, Boston, Massachusetts, USA
- Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA
| | - Daniel Okin
- Division of Pulmonary and Critical Care, Massachusetts General Hospital, Boston, Massachusetts, USA
- Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
| | - Elena Crestani
- Division of Immunology, Boston Children’s Hospital, Boston, Massachusetts, USA
- Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA
| | - Jason Fong
- Division of Immunology, Boston Children’s Hospital, Boston, Massachusetts, USA
- Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA
| | - Tsz Man Chan Fion
- Division of Immunology, Boston Children’s Hospital, Boston, Massachusetts, USA
- Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA
| | - Merve Nida Gokbak
- Division of Immunology, Boston Children’s Hospital, Boston, Massachusetts, USA
- Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA
| | - Hani Harb
- Division of Immunology, Boston Children’s Hospital, Boston, Massachusetts, USA
- Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA
- Institute for Medical Microbiology and Virology, Technical University Dresden, Germany
| | - Wanda Phipatanakul
- Division of Immunology, Boston Children’s Hospital, Boston, Massachusetts, USA
- Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA
| | - Luca Marri
- Department of Internal Medicine, Unit of Clinical Immunology and Translational Medicine, University of Genova, Italy
- Clinical Immunology Division, IRCCS-San Martino Hospital-Genova
| | - Chiara Vassallo
- Clinical Immunology Division, IRCCS-San Martino Hospital-Genova
| | | | - Minsik Kim
- Division of Pulmonary and Critical Care, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Hui-Yu Sui
- Division of Pulmonary and Critical Care, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Lorenzo Berra
- Department of Anaesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Marcia B. Goldberg
- Infectious Diseases Division, Massachusetts General Hospital, Boston, Massachusetts, USA
- Department of Microbiology, Harvard Medical School, Boston, Massachusetts, USA
| | - Claudia Angelini
- Istituto per le Applicazioni del Calcolo “M. Picone”, Consiglio Nazionale delle Ricerche, Naples, Italy
| | - Raffaele De Palma
- Department of Internal Medicine, Unit of Clinical Immunology and Translational Medicine, University of Genova, Italy
- CNR-Institute of Biomolecular Chemistry (IBC), Via Campi Flegrei 34, 80078 Pozzuoli, Napoli, Italy
| | - Talal A. Chatila
- Division of Immunology, Boston Children’s Hospital, Boston, Massachusetts, USA
- Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA
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16
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Chan FHM, Yeap HW, Liu Z, Rosli SN, Low KE, Bonne I, Wu Y, Chong SZ, Chen KW. Plasticity of cell death pathways ensures GSDMD activation during Yersinia pseudotuberculosis infection. Cell Rep 2025; 44:115216. [PMID: 39823227 DOI: 10.1016/j.celrep.2024.115216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 10/30/2024] [Accepted: 12/26/2024] [Indexed: 01/19/2025] Open
Abstract
Macrophages express pattern recognition and cytokine receptors that mediate proinflammatory signal transduction pathways to combat microbial infection. To retaliate against such responses, pathogenic microorganisms have evolved multiple strategies to impede innate immune signaling. Recent studies demonstrated that YopJ suppression of TAK1 signaling during Yersinia pseudotuberculosis infection promotes the assembly of a RIPK1-dependent death-inducing complex that enables caspase-8 to directly cleave and activate gasdermin D (GSDMD). However, whether and how macrophages respond to Yersinia infection in the absence of YopJ or caspase-8 activity remains unclear. Here, we demonstrate that loss of YopJ or its catalytic activity triggers non-canonical inflammasome activation in macrophages and that caspase-11 is required to restrict the bacterial burden in vivo. Under conditions of low caspase-8 activity, wild-type Y. pseudotuberculosis invades macrophages and accesses the cytosol, leading to non-canonical inflammasome activation. Thus, our study highlights the plasticity of death pathways to ensure GSDMD activation during Yersinia infection.
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Affiliation(s)
- Felicia Hui Min Chan
- Immunology Translational Research Programme, Life Sciences Institute, National University of Singapore, Singapore 117456, Singapore; Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545, Singapore
| | - Hui Wen Yeap
- Immunology Translational Research Programme, Life Sciences Institute, National University of Singapore, Singapore 117456, Singapore; Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545, Singapore
| | - Zonghan Liu
- Immunology Translational Research Programme, Life Sciences Institute, National University of Singapore, Singapore 117456, Singapore; Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545, Singapore
| | - Safwah Nasuha Rosli
- Immunology Translational Research Programme, Life Sciences Institute, National University of Singapore, Singapore 117456, Singapore; Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545, Singapore
| | - Kay En Low
- Electron Microscopy Unit, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117549, Singapore
| | - Isabelle Bonne
- Immunology Translational Research Programme, Life Sciences Institute, National University of Singapore, Singapore 117456, Singapore; Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545, Singapore; Electron Microscopy Unit, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117549, Singapore
| | - Yixuan Wu
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A(∗)STAR), 8A Biomedical Grove, Immunos, Singapore 138648, Republic of Singapore
| | - Shu Zhen Chong
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545, Singapore; Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A(∗)STAR), 8A Biomedical Grove, Immunos, Singapore 138648, Republic of Singapore
| | - Kaiwen W Chen
- Immunology Translational Research Programme, Life Sciences Institute, National University of Singapore, Singapore 117456, Singapore; Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117545, Singapore.
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17
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Badii M, Nica V, Straton AR, Kischkel B, Gaal O, Cabău G, Klück V, Hotea I, Novakovic B, Pamfil C, Rednic S, Netea MG, Popp RA, Joosten LAB, Crișan TO. Downregulation of type I interferon signalling pathway by urate in primary human PBMCs. Immunology 2025; 174:100-112. [PMID: 39354748 PMCID: PMC11652411 DOI: 10.1111/imm.13858] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Accepted: 08/23/2024] [Indexed: 10/03/2024] Open
Abstract
Type I interferons (IFN1s) mediate innate responses to microbial stimuli and regulate interleukin (IL)-1 and IL-1 receptor antagonist (Ra) production in human cells. This study explores interferon-stimulated gene (ISG) alterations in the transcriptome of patients with gout and stimulated human primary cells in vitro in relation to serum urate concentrations. Peripheral blood mononuclear cells (PBMCs) and monocytes of patients with gout were primed in vitro with soluble urate, followed by lipopolysaccharide (LPS) stimulation. Separately, PBMCs were stimulated with various toll-like receptor (TLR) ligands. RNA sequencing and IL-1Ra cytokine measurement were performed. STAT1 phosphorylation was assessed in urate-treated monocytes. Cytokine responses to IFN-β were evaluated in PBMCs cultured with or without urate and restimulated with LPS and monosodium urate (MSU) crystals. Transcriptomics revealed suppressed IFN-related signalling pathways in urate-exposed PBMCs or monocytes which was supported by diminishment of phosphorylated STAT1. The stimulation of PBMCs with IFN-β did not modify the urate-induced inflammation. Interestingly, in vivo, serum urate concentrations were inversely correlated to in vitro ISG expression upon stimulations with TLR ligands. These findings support a deficient IFN1 signalling in the presence of elevated serum urate concentrations, which could translate to increased susceptibility to infections.
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Affiliation(s)
- Medeea Badii
- Department of Medical GeneticsIuliu Hațieganu University of Medicine and PharmacyCluj‐NapocaRomania
- Department of Internal Medicine and Research Institute for Medical InnovationRadboud University Medical CentreNijmegenThe Netherlands
| | - Valentin Nica
- Department of Medical GeneticsIuliu Hațieganu University of Medicine and PharmacyCluj‐NapocaRomania
| | - Ancuța R. Straton
- Department of Medical GeneticsIuliu Hațieganu University of Medicine and PharmacyCluj‐NapocaRomania
| | - Brenda Kischkel
- Department of Internal Medicine and Research Institute for Medical InnovationRadboud University Medical CentreNijmegenThe Netherlands
| | - Orsolya Gaal
- Department of Medical GeneticsIuliu Hațieganu University of Medicine and PharmacyCluj‐NapocaRomania
- Department of Internal Medicine and Research Institute for Medical InnovationRadboud University Medical CentreNijmegenThe Netherlands
| | - Georgiana Cabău
- Department of Medical GeneticsIuliu Hațieganu University of Medicine and PharmacyCluj‐NapocaRomania
| | - Viola Klück
- Department of Internal Medicine and Research Institute for Medical InnovationRadboud University Medical CentreNijmegenThe Netherlands
| | - Ioana Hotea
- Department of Medical GeneticsIuliu Hațieganu University of Medicine and PharmacyCluj‐NapocaRomania
| | - Boris Novakovic
- Murdoch Children's Research Institute and Department of PaediatricsUniversity of Melbourne, Royal Children's HospitalParkvilleVictoriaAustralia
| | - Cristina Pamfil
- Department of RheumatologyIuliu Hațieganu University of Medicine and PharmacyCluj‐NapocaRomania
| | - Simona Rednic
- Department of RheumatologyIuliu Hațieganu University of Medicine and PharmacyCluj‐NapocaRomania
| | - Mihai G. Netea
- Department of Internal Medicine and Research Institute for Medical InnovationRadboud University Medical CentreNijmegenThe Netherlands
| | - Radu A. Popp
- Department of Medical GeneticsIuliu Hațieganu University of Medicine and PharmacyCluj‐NapocaRomania
| | - Leo A. B. Joosten
- Department of Medical GeneticsIuliu Hațieganu University of Medicine and PharmacyCluj‐NapocaRomania
- Department of Internal Medicine and Research Institute for Medical InnovationRadboud University Medical CentreNijmegenThe Netherlands
| | - Tania O. Crișan
- Department of Medical GeneticsIuliu Hațieganu University of Medicine and PharmacyCluj‐NapocaRomania
- Department of Internal Medicine and Research Institute for Medical InnovationRadboud University Medical CentreNijmegenThe Netherlands
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18
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Zheng R, Meng D, Hao N, Wang H, Peng W, Wang L, Wei Y. Yak IFNβ-3 enhances macrophage activity and attenuates Klebsiella pneumoniae infection. Int Immunopharmacol 2024; 143:113467. [PMID: 39486177 DOI: 10.1016/j.intimp.2024.113467] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2024] [Revised: 09/19/2024] [Accepted: 10/19/2024] [Indexed: 11/04/2024]
Abstract
Interferon-β (IFNβ) is an important member of the type I interferon family and plays key roles in antiviral response and treatment of autoimmune disease. However, the immunomodulation and antimicrobial potential of yak IFNβ3 protein are still unclear. In the current study, the 558 bp long cDNA sequence of the yak IFNβ3 gene was amplified and successfully expressed in a prokaryotic system. The mRNA expression level of IFNβ3 in yak spleen was higher than in heart, liver, lung and kidney. The minimum inhibitory concentration of recombinant IFNβ3 protein against Klebsiella pneumoniae was determined to be 64 μg/mL. The activity, phagocytosis, and nucleic acid intensity of yak macrophages were significantly increased by IFNβ3 protein (P < 0.05). In addition, the vitality of macrophages infected with Klebsiella pneumoniae was significantly increased by IFNβ3 protein (P < 0.05). The IFNβ3 protein significantly reduced the release of nitric oxide (NO) from macrophages infected with Klebsiella pneumoniae (P < 0.05). The mRNA levels of Capg, Man2b1, Mrc-1, γ-actin and Marco in macrophages were upregulated by IFNβ3 protein (P < 0.05). The contents of aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) in the serum of mice after Klebsiella pneumoniae infection were reduced by IFNβ3 protein (P < 0.05). The lung and kidney injuries in mice induced by Klebsiella pneumoniae infection were alleviated by IFNβ3 protein. In summary, the yak IFNβ3 protein enhanced macrophage activity and reduced the damage caused by Klebsiella pneumoniae infection in mice.
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Affiliation(s)
- Rui Zheng
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Ministry of Education, Southwest Minzu University, Chengdu 610041, China.
| | - Defei Meng
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Ministry of Education, Southwest Minzu University, Chengdu 610041, China.
| | - Ninghao Hao
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Ministry of Education, Southwest Minzu University, Chengdu 610041, China.
| | - Haipeng Wang
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Ministry of Education, Southwest Minzu University, Chengdu 610041, China.
| | - Wenli Peng
- Science, Technology, Agriculture and Animal Husbandry Bureau of Hongyuan County, Aba Prefecture 624000, China.
| | - Li Wang
- Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Ministry of Education, Southwest Minzu University, Chengdu 610041, China.
| | - Yong Wei
- Sichuan Academy of Animal Husbandry Science, Chengdu 610066, China.
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19
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Millar JE, Craven TH, Shankar-Hari M. Steroids and Immunomodulatory Therapies for Acute Respiratory Distress Syndrome. Clin Chest Med 2024; 45:885-894. [PMID: 39443005 DOI: 10.1016/j.ccm.2024.08.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2024]
Abstract
Acute respiratory distress syndrome (ARDS) is characterized by a dysregulated immune response to infection or injury. This framework has driven long-standing interest in immunomodulatory therapies as treatments for ARDS. In this narrative review, we first define what constitutes a dysregulated immune response in ARDS. In this context, we describe the rationale and available evidence for immunomodulatory therapies studied in randomized controlled trials of ARDS patients to date. Finally, we address factors that have contributed to the failure to develop therapies in the past and highlight current and future developments designed to address them.
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Affiliation(s)
- Jonathan E Millar
- Centre for Inflammation Research, Institute for Repair and Regeneration, University of Edinburgh, Edinburgh EH16 4UU, UK; Department of Critical Care, Intensive Care Unit, Queen Elizabeth University Hospital, Glasgow, UK
| | - Thomas H Craven
- Centre for Inflammation Research, Institute for Repair and Regeneration, University of Edinburgh, Edinburgh EH16 4UU, UK; Department of Critical Care, Royal Infirmary of Edinburgh, Edinburgh, UK
| | - Manu Shankar-Hari
- Centre for Inflammation Research, Institute for Repair and Regeneration, University of Edinburgh, Edinburgh EH16 4UU, UK; Department of Critical Care, Royal Infirmary of Edinburgh, Edinburgh, UK.
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20
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Fan H, Fu Q, Du G, Qin L, Shi X, Wang D, Yang Y. Microglial Mayhem NLRP3 Inflammasome's Role in Multiple Sclerosis Pathology. CNS Neurosci Ther 2024; 30:e70135. [PMID: 39690733 DOI: 10.1111/cns.70135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 09/29/2024] [Accepted: 11/05/2024] [Indexed: 12/19/2024] Open
Abstract
INTRODUCTION This review delves into the intricate relationship between NLR inflammasomes, particularly the NLRP3 inflammasome, and the immune-mediated neurodegenerative disease, multiple sclerosis (MS). While the precise etiology of MS remains elusive, compelling research underscores the pivotal role of the immune response in disease progression. Notably, recent investigations highlight the significant involvement of NLRP3 inflammasomes in various autoimmune diseases, prompting an in-depth exploration of their impact on MS. METHOD The review focuses on elucidating the activation mechanism of NLRP3 inflammasomes within microglia/macrophages (MG/MФ), examining how this activation promotes an inflammatory response that exacerbates neuronal damage in MS. A comprehensive analysis of existing literature and research findings forms the basis for understanding the intricate interplay between NLRP3 inflammasomes and MS pathogenesis. RESULTS Synthesizing current research, the review provides insight into the pivotal role played by NLR inflammasomes, specifically NLRP3, in MS. Emphasis is placed on the inflammatory response orchestrated by activated MG/MФ, elucidating the cascade that perpetuates neuronal damage in the disease. CONCLUSIONS This review concludes by consolidating key findings and offering a nuanced perspective on the role of NLRP3 inflammasomes in MS pathogenesis. The detailed exploration of the activation process within MG/MФ provides a foundation for understanding the disease's underlying mechanisms. Furthermore, the review sets the stage for potential therapeutic strategies targeting NLRP3 inflammasomes in the pursuit of MS treatment.
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Affiliation(s)
- Hua Fan
- Office of Research & Innovation, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
| | - Qizhi Fu
- Department of Intensive Medicine, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
| | - Ganqin Du
- Department of Neurology, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
| | - Ling Qin
- Department of Hematology, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
| | - Xiaofei Shi
- Department of Rheumatology and Immunology, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
| | - Dongmei Wang
- School of Basic Medical Sciences, Henan University of Science and Technology, Luoyang, China
| | - Yanhui Yang
- Department of Emergency Medicine, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, China
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21
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Huang J, Wang Y, Jia X, Zhao C, Zhang M, Bao M, Fu P, Cheng C, Shi R, Zhang X, Cui J, Wan G, Xu A. The human disease-associated gene ZNFX1 controls inflammation through inhibition of the NLRP3 inflammasome. EMBO J 2024; 43:5469-5493. [PMID: 39333773 PMCID: PMC11574294 DOI: 10.1038/s44318-024-00236-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 08/13/2024] [Accepted: 08/20/2024] [Indexed: 09/30/2024] Open
Abstract
Inherited deficiency of zinc finger NFX1-type containing 1 (ZNFX1), a dsRNA virus sensor, is associated with severe familial immunodeficiency, multisystem inflammatory disease, increased susceptibility to viruses, and early mortality. However, limited treatments for patients with pathological variants of ZNFX1 exist due to an incomplete understanding of the diseases resulting from ZNFX1 mutations. Here, we demonstrate that ZNFX1 specifically inhibits the activation of the NLR family pyrin domain-containing protein 3 (NLRP3) inflammasome in response to NLRP3 activators both in vitro and in vivo. ZNFX1 retains NLRP3 in the cytoplasm and prevents its accumulation in the TGN38 + /TGN46+ vesicles in the resting state. Upon NLRP3 inflammasome activation, ZNFX1 is cleaved by caspase-1, establishing a feed-forward loop that promotes NLRP3 accumulation in the trans-Golgi network (TGN) and amplifies the activity of the downstream cascade. Expression of wild-type ZNFX1, but not of ZNFX1 with human pathogenic mutations, rescues the impairment of NLRP3 inflammasome inhibition. Our findings reveal a dual role of ZNFX1 in virus sensing and suppression of inflammation, which may become valuable for the development of treatments for ZNFX1 mutation-related diseases.
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Affiliation(s)
- Jing Huang
- Guangdong Provincial Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong, 510275, China
| | - Yao Wang
- Beijing Research Institute of Chinese Medicine, School of Life Science, Beijing University of Chinese Medicine, Beijing, 100029, China.
| | - Xin Jia
- Beijing Research Institute of Chinese Medicine, School of Life Science, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Changfeng Zhao
- Guangdong Provincial Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong, 510275, China
| | - Meiqi Zhang
- Beijing Research Institute of Chinese Medicine, School of Life Science, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Mi Bao
- Guangdong Provincial Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong, 510275, China
| | - Pan Fu
- Guangdong Provincial Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong, 510275, China
| | - Cuiqin Cheng
- Beijing Research Institute of Chinese Medicine, School of Life Science, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Ruona Shi
- CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong, 510530, China
- Center for Cell Lineage and Atlas, BioLand Laboratory, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, Guangdong, 510530, China
| | - Xiaofei Zhang
- CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, GIBH-HKU Guangdong-Hong Kong Stem Cell and Regenerative Medicine Research Centre, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong, 510530, China
- Center for Cell Lineage and Atlas, BioLand Laboratory, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, Guangdong, 510530, China
| | - Jun Cui
- Guangdong Provincial Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong, 510275, China
| | - Gang Wan
- Guangdong Provincial Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong, 510275, China.
| | - Anlong Xu
- Guangdong Provincial Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong, 510275, China.
- Beijing Research Institute of Chinese Medicine, School of Life Science, Beijing University of Chinese Medicine, Beijing, 100029, China.
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22
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Porsch F, Binder CJ. Autoimmune diseases and atherosclerotic cardiovascular disease. Nat Rev Cardiol 2024; 21:780-807. [PMID: 38937626 DOI: 10.1038/s41569-024-01045-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/28/2024] [Indexed: 06/29/2024]
Abstract
Autoimmune diseases are associated with a dramatically increased risk of atherosclerotic cardiovascular disease and its clinical manifestations. The increased risk is consistent with the notion that atherogenesis is modulated by both protective and disease-promoting immune mechanisms. Notably, traditional cardiovascular risk factors such as dyslipidaemia and hypertension alone do not explain the increased risk of cardiovascular disease associated with autoimmune diseases. Several mechanisms have been implicated in mediating the autoimmunity-associated cardiovascular risk, either directly or by modulating the effect of other risk factors in a complex interplay. Aberrant leukocyte function and pro-inflammatory cytokines are central to both disease entities, resulting in vascular dysfunction, impaired resolution of inflammation and promotion of chronic inflammation. Similarly, loss of tolerance to self-antigens and the generation of autoantibodies are key features of autoimmunity but are also implicated in the maladaptive inflammatory response during atherosclerotic cardiovascular disease. Therefore, immunomodulatory therapies are potential efficacious interventions to directly reduce the risk of cardiovascular disease, and biomarkers of autoimmune disease activity could be relevant tools to stratify patients with autoimmunity according to their cardiovascular risk. In this Review, we discuss the pathophysiological aspects of the increased cardiovascular risk associated with autoimmunity and highlight the many open questions that need to be answered to develop novel therapies that specifically address this unmet clinical need.
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Affiliation(s)
- Florentina Porsch
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
| | - Christoph J Binder
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
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23
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Xu C, Jing W, Liu C, Yuan B, Zhang X, Liu L, Zhang F, Chen P, Liu Q, Wang H, Du X. Cytoplasmic DNA and AIM2 inflammasome in RA: where they come from and where they go? Front Immunol 2024; 15:1343325. [PMID: 39450183 PMCID: PMC11499118 DOI: 10.3389/fimmu.2024.1343325] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Accepted: 09/23/2024] [Indexed: 10/26/2024] Open
Abstract
Rheumatoid arthritis is a chronic autoimmune disease of undetermined etiology characterized by symmetric synovitis with predominantly destructive and multiple joint inflammation. Cytoplasmic DNA sensors that recognize protein molecules that are not themselves or abnormal dsDNA fragments play an integral role in the generation and perpetuation of autoimmune diseases by activating different signaling pathways and triggering innate immune signaling pathways and host defenses. Among them, melanoma deficiency factor 2 (AIM2) recognizes damaged DNA and double-stranded DNA and binds to them to further assemble inflammasome, initiating the innate immune response and participating in the pathophysiological process of rheumatoid arthritis. In this article, we review the research progress on the source of cytoplasmic DNA, the mechanism of assembly and activation of AIM2 inflammasome, and the related roles of other cytoplasmic DNA sensors in rheumatoid arthritis.
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Affiliation(s)
- Conghui Xu
- Department of Acupuncture-Moxibustion and Tuina, Gansu University of Chinese Medicine, Lanzhou, China
| | - Weiyao Jing
- Department of Acupuncture-Moxibustion and Tuina, Gansu University of Chinese Medicine, Lanzhou, China
| | - Cui Liu
- Department of Acupuncture-Moxibustion and Tuina, Gansu University of Chinese Medicine, Lanzhou, China
| | - Bo Yuan
- Department of Acupuncture and Pain, Affiliated Hospital of Gansu University of Traditional Chinese Medicine (TCM), Lanzhou, China
| | - Xinghua Zhang
- Department of Acupuncture, Gansu Provincial Hospital of Traditional Chinese Medicine, Lanzhou, China
| | - Limei Liu
- Department of Zheng's Acupuncture, Affiliated Hospital of Gansu University of Traditional Chinese Medicine (TCM), Lanzhou, China
| | - Fengfan Zhang
- Department of Rheumatic and Bone Disease, Gansu Provincial Hospital of Traditional Chinese Medicine (TCM), Lanzhou, China
| | - Ping Chen
- Department of Rheumatic and Bone Disease, Gansu Provincial Hospital of Traditional Chinese Medicine (TCM), Lanzhou, China
| | - Qiang Liu
- Department of Acupuncture-Moxibustion and Tuina, Gansu University of Chinese Medicine, Lanzhou, China
| | - Haidong Wang
- Department of Rheumatic and Bone Disease, Gansu Provincial Hospital of Traditional Chinese Medicine (TCM), Lanzhou, China
| | - Xiaozheng Du
- Department of Acupuncture-Moxibustion and Tuina, Gansu University of Chinese Medicine, Lanzhou, China
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24
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Tang J, Wang X, Chen S, Chang T, Gu Y, Zhang F, Hou J, Luo Y, Li M, Huang J, Liu M, Zhang L, Wang Y, Shen X, Xu L. Disruption of glucose homeostasis by bacterial infection orchestrates host innate immunity through NAD +/NADH balance. Cell Rep 2024; 43:114648. [PMID: 39167491 DOI: 10.1016/j.celrep.2024.114648] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 06/25/2024] [Accepted: 08/01/2024] [Indexed: 08/23/2024] Open
Abstract
Metabolic reprogramming is crucial for activating innate immunity in macrophages, and the accumulation of immunometabolites is essential for effective defense against infection. The NAD+/NADH (ratio of nicotinamide adenine dinucleotide and its reduced counterpart) redox couple serves as a critical node that integrates metabolic pathways and signaling events, but how this metabolite couple engages macrophage activation remains unclear. Here, we show that the NAD+/NADH ratio serves as a molecular signal that regulates proinflammatory responses and type I interferon (IFN) responses divergently. Salmonella Typhimurium infection leads to a decreased NAD+/NADH ratio by inducing the accumulation of NADH. Further investigation shows that an increased NAD+/NADH ratio correlates with attenuated proinflammatory responses and enhanced type I IFN responses. Conversely, a decreased NAD+/NADH ratio is linked to intensified proinflammatory responses and restrained type I IFN responses. These results show that the NAD+/NADH ratio is an essential cell-intrinsic factor that orchestrates innate immunity, which enhances our understanding of how metabolites fine-tune innate immunity.
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Affiliation(s)
- Jingjing Tang
- State Key Laboratory for Crop Stress Resistance and High-Efficiency Production, Shaanxi Key Laboratory of Agricultural and Environmental Microbiology, College of Life Sciences, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Xiao Wang
- State Key Laboratory for Crop Stress Resistance and High-Efficiency Production, Shaanxi Key Laboratory of Agricultural and Environmental Microbiology, College of Life Sciences, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Shukun Chen
- State Key Laboratory for Crop Stress Resistance and High-Efficiency Production, Shaanxi Key Laboratory of Agricultural and Environmental Microbiology, College of Life Sciences, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Tianyuan Chang
- State Key Laboratory for Crop Stress Resistance and High-Efficiency Production, Shaanxi Key Laboratory of Agricultural and Environmental Microbiology, College of Life Sciences, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Yanchao Gu
- State Key Laboratory for Crop Stress Resistance and High-Efficiency Production, Shaanxi Key Laboratory of Agricultural and Environmental Microbiology, College of Life Sciences, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Fuhua Zhang
- State Key Laboratory for Crop Stress Resistance and High-Efficiency Production, Shaanxi Key Laboratory of Agricultural and Environmental Microbiology, College of Life Sciences, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Jing Hou
- State Key Laboratory for Crop Stress Resistance and High-Efficiency Production, Shaanxi Key Laboratory of Agricultural and Environmental Microbiology, College of Life Sciences, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Yi Luo
- State Key Laboratory for Crop Stress Resistance and High-Efficiency Production, Shaanxi Key Laboratory of Agricultural and Environmental Microbiology, College of Life Sciences, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Mengyuan Li
- State Key Laboratory for Crop Stress Resistance and High-Efficiency Production, Shaanxi Key Laboratory of Agricultural and Environmental Microbiology, College of Life Sciences, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Jianan Huang
- State Key Laboratory for Crop Stress Resistance and High-Efficiency Production, Shaanxi Key Laboratory of Agricultural and Environmental Microbiology, College of Life Sciences, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Mohua Liu
- State Key Laboratory for Crop Stress Resistance and High-Efficiency Production, Shaanxi Key Laboratory of Agricultural and Environmental Microbiology, College of Life Sciences, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Lei Zhang
- State Key Laboratory for Crop Stress Resistance and High-Efficiency Production, Shaanxi Key Laboratory of Agricultural and Environmental Microbiology, College of Life Sciences, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Yao Wang
- State Key Laboratory for Crop Stress Resistance and High-Efficiency Production, Shaanxi Key Laboratory of Agricultural and Environmental Microbiology, College of Life Sciences, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Xihui Shen
- State Key Laboratory for Crop Stress Resistance and High-Efficiency Production, Shaanxi Key Laboratory of Agricultural and Environmental Microbiology, College of Life Sciences, Northwest A&F University, Yangling, Shaanxi 712100, China.
| | - Lei Xu
- State Key Laboratory for Crop Stress Resistance and High-Efficiency Production, Shaanxi Key Laboratory of Agricultural and Environmental Microbiology, College of Life Sciences, Northwest A&F University, Yangling, Shaanxi 712100, China.
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25
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Leya M, Yang D, Bao THTN, Jeong H, Oh SI, Kim JH, Kim JW, Kim B. The role of 2'-5'-oligoadenylate synthase-like protein (OASL1) in biliary and hepatotoxin-induced liver injury in mice. Sci Rep 2024; 14:21873. [PMID: 39300174 PMCID: PMC11413013 DOI: 10.1038/s41598-024-72465-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Accepted: 09/08/2024] [Indexed: 09/22/2024] Open
Abstract
Following an injury, the liver embarks on a process that drives the accumulation and reformation of the extracellular matrix, leading to hepatic fibrosis. Type I interferons (IFNs), including IFN-α and IFN-β, play a crucial role in averting chronic liver injury through the activation of IFN-stimulated genes (ISGs), which are instrumental in sculpting adaptive immunity. The role of 2'-5'-oligoadenylate synthase-like protein 1 (OASL1), an antiviral ISG, in the context of liver fibrosis remains to be elucidated. To elicit liver fibrosis, a diet containing 0.1% diethoxycarbonyl-1,4-dihydrocollidine (DDC) and carbon tetrachloride (CCl4) were employed to induce cholestatic- and hepatotoxin-mediated liver fibrosis, respectively. Histological analyses of both models revealed that OASL1-/- mice exhibited reduced liver damage and, consequently, expressed lower levels of fibrotic mediators, notably α-smooth muscle actin. OASL1-/- mice demonstrated significantly elevated IFN-α and IFN-β mRNA levels, regulated by the IFN regulatory factor 7 (IRF7). Additionally, OASL1-/- ameliorated chronic liver fibrosis through the modulation of nuclear factor-κB (NF-κB) signaling. The effect of OASL1 on type I IFN production in acute liver damage was further explored and OASL1-/- mice consistently showed lower alanine transaminase levels and pro-inflammatory cytokines, but IFN-α and IFN-β mRNA levels were upregulated, leading to amelioration of acute liver injury. Additionally, the study discovered that F4/80-positive cells were observed more frequently in OASL1-/- CCl4 acutely treated mice. This implies that there is a significant synergy in the function of macrophages and OASL1 deficiency. These results demonstrate that in instances of liver injury, OASL1 inhibits the production of type I IFN by modulating the NF-κB signaling pathway, thereby worsening disease.
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Affiliation(s)
- Mwense Leya
- Biosafety Research Institute and College of Veterinary Medicine, Jeonbuk National University, 79, Gobong-Ro, Iksan-Si, Jeollabuk-Do, 54596, Republic of Korea
- School of Veterinary Medicine, University of Namibia, P.O. Box 13301, Windhoek, 10005, Namibia
| | - Daram Yang
- Biosafety Research Institute and College of Veterinary Medicine, Jeonbuk National University, 79, Gobong-Ro, Iksan-Si, Jeollabuk-Do, 54596, Republic of Korea
| | - Tien Huyen Ton Nu Bao
- Biosafety Research Institute and College of Veterinary Medicine, Jeonbuk National University, 79, Gobong-Ro, Iksan-Si, Jeollabuk-Do, 54596, Republic of Korea
| | - Hyuneui Jeong
- Biosafety Research Institute and College of Veterinary Medicine, Jeonbuk National University, 79, Gobong-Ro, Iksan-Si, Jeollabuk-Do, 54596, Republic of Korea
| | - Sang-Ik Oh
- Biosafety Research Institute and College of Veterinary Medicine, Jeonbuk National University, 79, Gobong-Ro, Iksan-Si, Jeollabuk-Do, 54596, Republic of Korea
| | - Jong-Hoon Kim
- Biosafety Research Institute and College of Veterinary Medicine, Jeonbuk National University, 79, Gobong-Ro, Iksan-Si, Jeollabuk-Do, 54596, Republic of Korea
| | - Jong-Won Kim
- Biosafety Research Institute and College of Veterinary Medicine, Jeonbuk National University, 79, Gobong-Ro, Iksan-Si, Jeollabuk-Do, 54596, Republic of Korea.
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, USA.
| | - Bumseok Kim
- Biosafety Research Institute and College of Veterinary Medicine, Jeonbuk National University, 79, Gobong-Ro, Iksan-Si, Jeollabuk-Do, 54596, Republic of Korea.
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26
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Huang C, Huangfu C, Bai Z, Zhu L, Shen P, Wang N, Li G, Deng H, Ma Z, Zhou W, Gao Y. Multifunctional carbomer based ferulic acid hydrogel promotes wound healing in radiation-induced skin injury by inactivating NLRP3 inflammasome. J Nanobiotechnology 2024; 22:576. [PMID: 39300534 PMCID: PMC11411768 DOI: 10.1186/s12951-024-02789-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Accepted: 08/20/2024] [Indexed: 09/22/2024] Open
Abstract
BACKGROUND Radiation-induced skin injury is a significant adverse reaction to radiotherapy. However, there is a lack of effective prevention and treatment methods for this complication. Ferulic acid (FA) has been identified as an effective anti-radiation agent. Conventional administrations of FA limit the reaching of it on skin. We aimed to develop a novel FA hydrogel to facilitate the use of FA in radiation-induced skin injury. METHODS We cross-linked carbomer 940, a commonly used adjuvant, with FA at concentrations of 5%, 10%, and 15%. Sweep source optical coherence tomography system, a novel skin structure evaluation method, was applied to investigate the influence of FA on radiation-induced skin injury. Calcein-AM/PI staining, CCK8 assay, hemolysis test and scratch test were performed to investigate the biocompatibility of FA hydrogel. The reducibility of DPPH and ABTS radicals by FA hydrogel was also performed. HE staining, Masson staining, laser Doppler blood flow monitor, and OCT imaging system are used to evaluate the degree of skin tissue damage. Potential differentially expressed genes were screened via transcriptome analysis. RESULTS Good biocompatibility and in vitro antioxidant ability of the FA hydrogels were observed. 10% FA hydrogel presented a better mechanical stability than 5% and 15% FA hydrogel. All three concentrations of FA remarkably promoted the recovery of radiation-induced skin injury by reducing inflammation, oxidative conidiation, skin blood flow, and accelerating skin tissue reconstruction, collagen deposition. FA hydrogel greatly inhibiting the levels of NLRP3, caspase-1, IL-18, pro-IL-1β and IL-1β in vivo and vitro levels through restraining the activation of NLRP3 inflammasome. Transcriptome analysis indicated that FA might regulate wound healing via targeting immune response, inflammatory response, cell migration, angiogenesis, hypoxia response, and cell matrix adhesion. CONCLUSIONS These findings suggest that the novel FA hydrogel is a promising therapeutic method for the prevention and treatment of radiation-induced skin injury patients.
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Affiliation(s)
- Congshu Huang
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, No. 27 Taiping Road, Beijing, 100850, China
- Department of Traditional Chinese medicine, Henan University of Chinese Medicine, No. 156 Jinshui East Road, Zhengzhou, 450046, China
| | - Chaoji Huangfu
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, No. 27 Taiping Road, Beijing, 100850, China
| | - Zhijie Bai
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, No. 27 Taiping Road, Beijing, 100850, China
| | - Long Zhu
- Qinghai University, No. 251 Ningda Road, Xining, 810016, China
| | - Pan Shen
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, No. 27 Taiping Road, Beijing, 100850, China
| | - Ningning Wang
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, No. 27 Taiping Road, Beijing, 100850, China
| | - Gaofu Li
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, No. 27 Taiping Road, Beijing, 100850, China
| | - Huifang Deng
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, No. 27 Taiping Road, Beijing, 100850, China
| | - Zengchun Ma
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, No. 27 Taiping Road, Beijing, 100850, China.
| | - Wei Zhou
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, No. 27 Taiping Road, Beijing, 100850, China.
| | - Yue Gao
- Department of Pharmaceutical Sciences, Beijing Institute of Radiation Medicine, No. 27 Taiping Road, Beijing, 100850, China.
- State Key Laboratory of Kidney Diseases, Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing, 100853, China.
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Peng X, Pu F, Zhou F, Dai X, Xu F, Wang J, Feng J, Xia P. Exploring expression levels of the cGAS-STING pathway genes in peripheral blood mononuclear cells of spinal tuberculosis patients. BMC Infect Dis 2024; 24:915. [PMID: 39232642 PMCID: PMC11373091 DOI: 10.1186/s12879-024-09815-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Accepted: 08/27/2024] [Indexed: 09/06/2024] Open
Abstract
BACKGROUND This study aimed to investigate the differential expression levels of the cGAS-STING pathway in peripheral blood mononuclear cells (PBMCs) of spinal tuberculosis (TB) patients with different progression and its feasibility as a diagnostic marker. METHODS Peripheral blood and medical records of 25 patients with spinal TB and 10 healthy individuals, were prospectively collected and analyzed. PBMCs and serum were extracted from peripheral blood and the expression levels of the cGAS-STING pathway in PBMCs were measured by real-time PCR (RT-PCR) and serum interferon β (IFN-β) expression levels were measured by enzyme-linked immunosorbent assay (ELISA). The expression of Interferon regulatory Factor 3 (IRF3) in PBMCs was measured using western blot. Statistical analysis was performed using the SPSS 26.0 statistical package. RESULTS The results showed that the expression level of the TANK-binding kinase 1 (TBK1) and IRF3 was significantly higher in PBMCs (P < 0.05), in patients with active lesions than in patients with stable lesions. The serum concentration of IFN-β was significantly higher in patients with active lesions (P = 0.028). Compared with healthy individuals, the expression level of the cGAS-STING pathway was elevated in PBMCs of TB patients (P < 0.05), and the difference in the expression level of IFN-β was not statistically significant (P > 0.05), and the serum IFN-β concentration was elevated (P < 0.05). The calculated AUC values for TBK1 and IRF3 in PBMCs, IFN-β in serum and erythrocyte sedimentation rate (ESR) to distinguish between patients with active and stable lesions were 0.732, 0.714, 0.839, and 0.714 respectively. CONCLUSIONS The expression level of TBK1 and IRF3 in PBMCs, and IFN-β in the serum of patients with spinal TB is positively correlated with disease activity. TBK1 has higher specificity and IFN-β in serum has higher sensitivity when used to differentiate between patients with active and stable lesions.
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Affiliation(s)
- Xianglin Peng
- Department of Orthopedics, Tongji Medical College, Traditional Chinese and Western Medicine Hospital of Wuhan, Huazhong University of Science and Technology, Wuhan, 430022, China
- Department of Orthopedics, Wuhan No.1 Hospital, Wuhan, 430022, China
| | - Feifei Pu
- Department of Orthopedics, Tongji Medical College, Traditional Chinese and Western Medicine Hospital of Wuhan, Huazhong University of Science and Technology, Wuhan, 430022, China
- Department of Orthopedics, Wuhan No.1 Hospital, Wuhan, 430022, China
| | - Fangzheng Zhou
- Department of Orthopedics, Tongji Medical College, Traditional Chinese and Western Medicine Hospital of Wuhan, Huazhong University of Science and Technology, Wuhan, 430022, China
- Department of Orthopedics, Wuhan No.1 Hospital, Wuhan, 430022, China
| | - Xiyong Dai
- Wuhan Pulmonary Hospital, Wuhan Institute for Tuberculosis Control, Wuhan, 430022, China
| | - Feng Xu
- Wuhan Pulmonary Hospital, Wuhan Institute for Tuberculosis Control, Wuhan, 430022, China
| | - Junwen Wang
- Department of Orthopedics, Wuhan Fourth Hospital, Puai Hospital, Wuhan, 430030, China
| | - Jing Feng
- Department of Orthopedics, Tongji Medical College, Traditional Chinese and Western Medicine Hospital of Wuhan, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Department of Orthopedics, Wuhan No.1 Hospital, Wuhan, 430022, China.
| | - Ping Xia
- Department of Orthopedics, Wuhan Fourth Hospital, Puai Hospital, Wuhan, 430030, China.
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Bhattacharya S, Chakraborty S, Manna D, Thakur P, Chakravorty N, Mukherjee B. Deciphering the intricate dynamics of inflammasome regulation in visceral and post-kala-azar dermal leishmaniasis: A meta-analysis of consistencies. Acta Trop 2024; 257:107313. [PMID: 38964632 DOI: 10.1016/j.actatropica.2024.107313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Revised: 06/27/2024] [Accepted: 07/01/2024] [Indexed: 07/06/2024]
Abstract
Post Kala-azar dermal leishmaniasis (PKDL) arises as a significant dermal sequel following Visceral leishmaniasis (VL) caused by protozoan parasite Leishmania donovani (LD). PKDL acts as a significant constrain for VL elimination serving as a crucial reservoir for LD. PKDL patients exhibit depigmented macular and papular lesions on their skin, which results in social discrimination due to loss of natural skin color. Inflammatory reactions, prevalent in both VL and PKDL, potentially lead to tissue damage in areas harboring the parasite. Disruption of the immune-inflammasomal network not only facilitates LD persistence but also leads to the skin hypopigmentation seen in PKDL, impacting social well-being. Activation of inflammasomal markers like STAT1, NLRP1, NLRP3, AIM2, CASP11, and NLRP12 have been identified as a common host-defense mechanism across various Leishmania infections. Conversely, Leishmania modulates inflammasome activation to sustain its presence within the host. Nevertheless, in specific instances of Leishmania infection, inflammasome activation can worsen disease pathology by promoting parasite proliferation and persistence. This study encompasses recent transcriptomic analyses conducted between 2016 and 2023 on human and murine subjects afflicted with VL/PKDL, elucidating significant alterations in inflammasomal markers in both conditions. It offers a comprehensive understanding how these markers contribute in disease progression, drawing upon available literature for logical analysis. Furthermore, our analysis identifies validated miRNA network that could potentially disrupt this crucial immune-inflammasomal network, thereby offering a plausible explanation on how secreted LD-factors could enable membrane-bound LD, isolated from the host cytoplasm, to modulate cytoplasmic inflammasomal markers. Insights from this study could guide the development of host-directed therapeutics to impede transmission and address hypopigmentation, thereby mitigating the social stigma associated with PKDL.
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Affiliation(s)
| | | | - Debolina Manna
- School of Medical Science and Technology, IIT Kharagpur, Kharagpur 721302, India
| | - Pradipti Thakur
- School of Medical Science and Technology, IIT Kharagpur, Kharagpur 721302, India
| | - Nishant Chakravorty
- School of Medical Science and Technology, IIT Kharagpur, Kharagpur 721302, India
| | - Budhaditya Mukherjee
- School of Medical Science and Technology, IIT Kharagpur, Kharagpur 721302, India.
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Apaza CJ, Cerezo JF, García-Tejedor A, Giménez-Bastida JA, Laparra-Llopis JM. Revisiting the Immunometabolic Basis for the Metabolic Syndrome from an Immunonutritional View. Biomedicines 2024; 12:1825. [PMID: 39200288 PMCID: PMC11352112 DOI: 10.3390/biomedicines12081825] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Revised: 07/11/2024] [Accepted: 08/06/2024] [Indexed: 09/02/2024] Open
Abstract
Metabolic syndrome (MetS) implies different conditions where insulin resistance constitutes a major hallmark of the disease. The disease incurs a high risk for the development of cardiovascular complications, and takes its toll in regard to the gut-liver axis (pancreas, primary liver and colorectal)-associated immunity. The modulation of immunometabolic responses by immunonutritional factors (IFs) has emerged as a key determinant of the gut-liver axis' metabolic and immune health. IFs from plant seeds have shown in vitro and pre-clinical effectiveness primarily in dealing with various immunometabolic and inflammatory diseases. Only recently have immunonutritional studies established the engagement of innate intestinal immunity to effectively control immune alterations in inflamed livers preceding the major features of the MetS. However, integrative analyses and the demonstration of causality between IFs and specific gut-liver axis-associated immunometabolic imbalances for the MetS remain ill-defined in the field. Herein, a better understanding of the IFs with a significant role in the MetS, as well as within the dynamic interplay in the functional differentiation of innate immune key effectors (i.e., monocytes/macrophages), worsening or improving the disease, could be of crucial relevance. The development of an adequate intermediary phenotype of these cells can significantly contribute to maintaining the function of Tregs and innate lymphoid cells for the prevention and treatment of MetS and associated comorbidities.
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Affiliation(s)
- César Jeri Apaza
- Madrid Institute for Advanced Studies in Food (IMDEA Food), Carretera Cantoblanco 8, 28049 Madrid, Spain
- Bioactivity and Nutritional Immunology Group (BIOINUT), Valencian International University (VIU), Pintor Sorolla 21, 46002 Valencia, Spain
| | - Juan Francisco Cerezo
- Madrid Institute for Advanced Studies in Food (IMDEA Food), Carretera Cantoblanco 8, 28049 Madrid, Spain
| | - Aurora García-Tejedor
- Bioactivity and Nutritional Immunology Group (BIOINUT), Valencian International University (VIU), Pintor Sorolla 21, 46002 Valencia, Spain
| | - Juan Antonio Giménez-Bastida
- Research Group on Quality, Safety and Bioactivity of Plant Foods, Campus de Espinardo, CEBAS-CSIC, P.O. Box 164, 30100 Murcia, Spain;
| | - José Moisés Laparra-Llopis
- Madrid Institute for Advanced Studies in Food (IMDEA Food), Carretera Cantoblanco 8, 28049 Madrid, Spain
- Bioactivity and Nutritional Immunology Group (BIOINUT), Valencian International University (VIU), Pintor Sorolla 21, 46002 Valencia, Spain
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Yadav S, El Hamra R, Alturki NA, Ariana A, Bhan A, Hurley K, Gaestel M, Blackshear PJ, Blais A, Sad S. Regulation of Zfp36 by ISGF3 and MK2 restricts the expression of inflammatory cytokines during necroptosis stimulation. Cell Death Dis 2024; 15:574. [PMID: 39117638 PMCID: PMC11310327 DOI: 10.1038/s41419-024-06964-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 07/29/2024] [Accepted: 07/31/2024] [Indexed: 08/10/2024]
Abstract
Necrosome activation following TLR- or cytokine receptor-signaling results in cell death by necroptosis which is characterized by the rupture of cell membranes and the consequent release of intracellular contents to the extracellular milieu. While necroptosis exacerbates various inflammatory diseases, the mechanisms through which the inflammatory responses are regulated are not clear. We show that the necrosome activation of macrophages results in an upregulation of various pathways, including the mitogen-activated protein kinase (MAPK) cascade, which results in an elevation of the inflammatory response and consequent expression of several cytokines and chemokines. Programming for this upregulation of inflammatory response occurs during the early phase of necrosome activation and proceeds independently of cell death but depends on the activation of the receptor-interacting protein kinase-1 (RipK1). Interestingly, necrosome activation also results in an upregulation of IFNβ, which in turn exerts an inhibitory effect on the maintenance of inflammatory response through the repression of MAPK-signaling and an upregulation of Zfp36. Activation of the interferon-induced gene factor-3 (ISGF3) results in the expression of ZFP36 (TTP), which induces the post-transcriptional degradation of mRNAs of various inflammatory cytokines and chemokines through the recognition of AU-rich elements in their 3'UTR. Furthermore, ZFP-36 inhibits IFNβ-, but not TNFα- induced necroptosis. Overall, these results reveal the molecular mechanism through which IFNβ, a pro-inflammatory cytokine, induces the expression of ZFP-36, which in turn inhibits necroptosis and halts the maintenance of the inflammatory response.
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Affiliation(s)
- Sahil Yadav
- Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Rayan El Hamra
- Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Norah A Alturki
- Clinical Laboratory Science Department, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Ardeshir Ariana
- Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Avni Bhan
- Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Kate Hurley
- Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Matthias Gaestel
- Institute of Cell Biochemistry, Hannover Medical School, Hannover, Germany
| | - Perry J Blackshear
- Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, North Carolina, United States of America
| | - Alexandre Blais
- Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- Ottawa Institute of Systems Biology, Ottawa, ON, Canada
- University of Ottawa, Centre for Infection Immunity and Inflammation, Ottawa, ON, Canada
- University of Ottawa Brain and Mind Research Institute, Ottawa, ON, Canada
| | - Subash Sad
- Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.
- University of Ottawa, Centre for Infection Immunity and Inflammation, Ottawa, ON, Canada.
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Han L, Sun X, Kong J, Li J, Feng K, Bai Y, Wang X, Zhu Z, Yang F, Chen Q, Zhang M, Yue B, Wang X, Fu L, Chen Y, Yang Q, Wang S, Xin Q, Sun N, Zhang D, Zhou Y, Gao Y, Zhao J, Jiang Y, Guo R. Multi-omics analysis reveals a feedback loop amplifying immune responses in acute graft-versus-host disease due to imbalanced gut microbiota and bile acid metabolism. J Transl Med 2024; 22:746. [PMID: 39113144 PMCID: PMC11308528 DOI: 10.1186/s12967-024-05577-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Accepted: 08/04/2024] [Indexed: 08/10/2024] Open
Abstract
Acute graft-versus-host disease (aGVHD) is primarily driven by allogeneic donor T cells associated with an altered composition of the host gut microbiome and its metabolites. The severity of aGVHD after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is not solely determined by the host and donor characteristics; however, the underlying mechanisms remain unclear. Using single-cell RNA sequencing, we decoded the immune cell atlas of 12 patients who underwent allo-HSCT: six with aGVHD and six with non-aGVHD. We performed a fecal microbiota (16SrRNA sequencing) analysis to investigate the fecal bacterial composition of 82 patients: 30 with aGVHD and 52 with non-aGVHD. Fecal samples from these patients were analyzed for bile acid metabolism. Through multi-omic analysis, we identified a feedback loop involving "immune cell-gut microbes-bile acid metabolites" contributing to heightened immune responses in patients with aGVHD. The dysbiosis of the gut microbiota and disruption of bile acid metabolism contributed to an exaggerated interleukin-1 mediated immune response. Our findings suggest that resistin and defensins are crucial in mitigating against aGVHD. Therefore, a comprehensive multi-omic atlas incorporating immune cells, gut microbes, and bile acid metabolites was developed in this study and used to propose novel, non-immunosuppressive approaches to prevent aGVHD.
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Affiliation(s)
- Lijie Han
- Translational Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Xianlei Sun
- Basic Medical Research Center, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Jingjing Kong
- Translational Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Jin Li
- Translational Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Kai Feng
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yanliang Bai
- Department of Hematology, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Zhengzhou, Henan, China
| | - Xianjing Wang
- Department of Hematology, The Third People's Hospital of Zhengzhou, Zhengzhou, 450000, Henan, China
| | - Zhenhua Zhu
- Department of Laboratory Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Fengyuan Yang
- Basic Medical Research Center, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Qingzhou Chen
- Department of Laboratory Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Mengmeng Zhang
- Translational Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Baohong Yue
- Department of Laboratory Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Xiaoqian Wang
- Department of Laboratory Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Liyan Fu
- Department of Laboratory Medicine, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Yaoyao Chen
- Department of Laboratory Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Qiankun Yang
- Department of Blood Transfusion, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Shuya Wang
- Department of Blood Transfusion, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Qingxuan Xin
- Department of Laboratory Medicine, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Nannan Sun
- Translational Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Danfeng Zhang
- Translational Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yiwei Zhou
- Translational Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yanxia Gao
- Department of Emergency Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Junwei Zhao
- Department of Laboratory Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
| | - Yong Jiang
- Henan Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine and Department of Emergency Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
| | - Rongqun Guo
- Translational Medical Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
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Hwang S, Eom YW, Kang SH, Baik SK, Kim MY. IFN-β Overexpressing Adipose-Derived Mesenchymal Stem Cells Mitigate Alcohol-Induced Liver Damage and Gut Permeability. Int J Mol Sci 2024; 25:8509. [PMID: 39126076 PMCID: PMC11313321 DOI: 10.3390/ijms25158509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Revised: 08/01/2024] [Accepted: 08/01/2024] [Indexed: 08/12/2024] Open
Abstract
Alcoholic liver disease (ALD) is a form of hepatic inflammation. ALD is mediated by gut leakiness. This study evaluates the anti-inflammatory effects of ASCs overexpressing interferon-beta (ASC-IFN-β) on binge alcohol-induced liver injury and intestinal permeability. In vitro, ASCs were transfected with a non-viral vector carrying the human IFN-β gene, which promoted hepatocyte growth factor (HGF) secretion in the cells. To assess the potential effects of ASC-IFN-β, C57BL/6 mice were treated with three oral doses of binge alcohol and were administered intraperitoneal injections of ASC-IFN-β. Mice treated with binge alcohol and administered ASC-IFN-β showed reduced liver injury and inflammation compared to those administered a control ASC. Analysis of intestinal tissue from ethanol-treated mice administered ASC-IFN-β also indicated decreased inflammation. Additionally, fecal albumin, blood endotoxin, and bacterial colony levels were reduced, indicating less gut leakiness in the binge alcohol-exposed mice. Treatment with HGF, but not IFN-β or TRAIL, mitigated the ethanol-induced down-regulation of cell death and permeability in Caco-2 cells. These results demonstrate that ASCs transfected with a non-viral vector to induce IFN-β overexpression have protective effects against binge alcohol-mediated liver injury and gut leakiness via HGF.
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Affiliation(s)
- Soonjae Hwang
- Department of Biochemistry, Lee Gil Ya Cancer and Diabetes Institute, College of Medicine, Gachon University, Incheon 21999, Republic of Korea;
- Regeneration Medicine Research Center, Wonju College of Medicine, Yonsei University, Wonju 26426, Gangwon-do, Republic of Korea; (Y.W.E.); (S.K.B.)
- Cell Therapy and Tissue Engineering Center, Wonju College of Medicine, Yonsei University, Wonju 26426, Gangwon-do, Republic of Korea
| | - Young Woo Eom
- Regeneration Medicine Research Center, Wonju College of Medicine, Yonsei University, Wonju 26426, Gangwon-do, Republic of Korea; (Y.W.E.); (S.K.B.)
- Cell Therapy and Tissue Engineering Center, Wonju College of Medicine, Yonsei University, Wonju 26426, Gangwon-do, Republic of Korea
| | - Seong Hee Kang
- Department of Internal Medicine, College of Medicine, Korea University, Seoul 02841, Republic of Korea;
| | - Soon Koo Baik
- Regeneration Medicine Research Center, Wonju College of Medicine, Yonsei University, Wonju 26426, Gangwon-do, Republic of Korea; (Y.W.E.); (S.K.B.)
- Department of Internal Medicine, Wonju College of Medicine, Yonsei University, Wonju 26426, Gangwon-do, Republic of Korea
| | - Moon Young Kim
- Regeneration Medicine Research Center, Wonju College of Medicine, Yonsei University, Wonju 26426, Gangwon-do, Republic of Korea; (Y.W.E.); (S.K.B.)
- Department of Internal Medicine, Wonju College of Medicine, Yonsei University, Wonju 26426, Gangwon-do, Republic of Korea
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Anes E, Azevedo-Pereira JM, Pires D. Role of Type I Interferons during Mycobacterium tuberculosis and HIV Infections. Biomolecules 2024; 14:848. [PMID: 39062562 PMCID: PMC11275242 DOI: 10.3390/biom14070848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 07/10/2024] [Accepted: 07/11/2024] [Indexed: 07/28/2024] Open
Abstract
Tuberculosis and AIDS remain two of the most relevant human infectious diseases. The pathogens that cause them, Mycobacterium tuberculosis (Mtb) and HIV, individually elicit an immune response that treads the line between beneficial and detrimental to the host. Co-infection further complexifies this response since the different cytokines acting on one infection might facilitate the dissemination of the other. In these responses, the role of type I interferons is often associated with antiviral mechanisms, while for bacteria such as Mtb, their importance and clinical relevance as a suitable target for manipulation are more controversial. In this article, we review the recent knowledge on how these interferons play distinct roles and sometimes have opposite consequences depending on the stage of the pathogenesis. We highlight the dichotomy between the acute and chronic infections displayed by both infections and how type I interferons contribute to an initial control of each infection individually, while their chronic induction, particularly during HIV infection, might facilitate Mtb primo-infection and progression to disease. We expect that further findings and their systematization will allow the definition of windows of opportunity for interferon manipulation according to the stage of infection, contributing to pathogen clearance and control of immunopathology.
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Affiliation(s)
- Elsa Anes
- Host-Pathogen Interactions Unit, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal; (J.M.A.-P.); (D.P.)
| | - José Miguel Azevedo-Pereira
- Host-Pathogen Interactions Unit, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal; (J.M.A.-P.); (D.P.)
| | - David Pires
- Host-Pathogen Interactions Unit, Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal; (J.M.A.-P.); (D.P.)
- Center for Interdisciplinary Research in Health, Católica Medical School, Universidade Católica Portuguesa, Estrada Octávio Pato, 2635-631 Rio de Mouro, Portugal
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Lyu S, Zhang T, Peng P, Cao D, Ma L, Yu Y, Dong Y, Qi X, Wei C. Involvement of cGAS/STING Signaling in the Pathogenesis of Candida albicans Keratitis: Insights From Genetic and Pharmacological Approaches. Invest Ophthalmol Vis Sci 2024; 65:13. [PMID: 38848078 PMCID: PMC11166223 DOI: 10.1167/iovs.65.6.13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Accepted: 05/14/2024] [Indexed: 06/13/2024] Open
Abstract
Purpose Fungal keratitis (FK) is an invasive corneal infection associated with significant risk to vision. Although the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) signaling pathway has been recognized for its role in defending against viral infections, its involvement in FK still remains largely unclear. This study sought to elucidate the contribution of the cGAS/STING signaling pathway to the pathogenesis of FK. Methods The expression of cGAS/STING signaling components was assessed in a murine model of Candida albicans keratitis through RNA sequencing, western blot analysis, immunofluorescence staining, and real-time PCR. Both genetic (utilizing Sting1gt/gt mice) and pharmacological (using C176) interventions were employed to inhibit STING activity, allowing for the evaluation of resultant pathogenic alterations in FK using slit-lamp examination, clinical scoring, hematoxylin and eosin (H&E) staining, fungal culture, and RNA sequencing. Subconjunctival administration of the NOD-like receptor protein 3 (NLRP3) inflammasome inhibitor MCC950 was performed to evaluate FK manifestations following STING activity blockade. Furthermore, the impact of the STING agonist diABZI on FK progression was investigated. Results Compared to uninfected corneas, those infected with C. albicans exhibited increased expression of cGAS/STING signaling components, as well as its elevated activity. Inhibiting cGAS/STING signaling exacerbated the advancement of FK, as evidenced by elevated clinical scores, augmented fungal load, and heightened inflammatory response, including NLRP3 inflammasome activation and pyroptosis. Pharmacological inhibition of the NLRP3 inflammasome effectively mitigated the exacerbated FK by suppressing STING activity. Conversely, pre-activation of STING exacerbated FK progression compared to the PBS control, characterized by increased fungal burden and reinforced inflammatory infiltration. Conclusions This study demonstrates the essential role of the cGAS/STING signaling pathway in FK pathogenesis and highlights the necessity of its proper activation for the host against FK.
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Affiliation(s)
- Shanmei Lyu
- Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao, China
| | - Ting Zhang
- Eye Hospital of Shandong First Medical University, Eye Institute of Shandong First Medical University, Jinan, Shandong, China
| | - Peng Peng
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao, China
| | - Dingwen Cao
- Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao, China
| | - Li Ma
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao, China
| | - Yang Yu
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao, China
| | - Yanling Dong
- Qingdao Eye Hospital of Shandong First Medical University, Eye Institute of Shandong First Medical University, Qingdao, China
| | - Xiaolin Qi
- Eye Hospital of Shandong First Medical University, Eye Institute of Shandong First Medical University, Jinan, Shandong, China
- School of Ophthalmology, Shandong First Medical University, Jinan, Shandong, China
| | - Chao Wei
- State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Eye Institute of Shandong First Medical University, Qingdao, China
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Díaz-Pino R, Rice GI, San Felipe D, Pepanashvili T, Kasher PR, Briggs TA, López-Castejón G. Type I interferon regulates interleukin-1beta and IL-18 production and secretion in human macrophages. Life Sci Alliance 2024; 7:e202302399. [PMID: 38527803 DOI: 10.26508/lsa.202302399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 03/12/2024] [Accepted: 03/13/2024] [Indexed: 03/27/2024] Open
Abstract
Inflammasomes are immune complexes whose activation leads to the release of pro-inflammatory cytokines IL-18 and IL-1β. Type I IFNs play a role in fighting infection and stimulate the expression of IFN-stimulated genes (ISGs) involved in inflammation. Despite the importance of these cytokines in inflammation, the regulation of inflammasomes by type I IFNs remains poorly understood. Here, we analysed RNA-sequencing data from patients with monogenic interferonopathies and found an up-regulation of several inflammasome-related genes. To investigate the effect of type I IFN on the inflammasome, we treated human monocyte-derived macrophages with IFN-α and observed an increase in CASP1 and GSDMD mRNA levels over time, whereas IL1B and NLRP3 were not directly correlated to IFN-α exposure time. IFN-α treatment reduced the release of mature IL-1β and IL-18, but not caspase-1, in response to ATP-mediated NLRP3 inflammasome activation, suggesting regulation occurs at cytokine expression levels and not the inflammasome itself. However, more studies are required to investigate how regulation by IFN-α occurs and impacts NLRP3 and other inflammasomes at both transcriptional and post-translational levels.
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Affiliation(s)
- Rodrigo Díaz-Pino
- Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK
- School of Biological Sciences, Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
| | - Gillian I Rice
- Department of Genomic Medicine, St Marys Hospital, Manchester Foundation Trust, Manchester, UK
- Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
| | - Diego San Felipe
- Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK
- School of Biological Sciences, Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
- Department of Physiology, Faculty of Medicine, Universidad Complutense de Madrid, Madrid, Spain
| | - Tamar Pepanashvili
- Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK
| | - Paul R Kasher
- Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK
- Geoffrey Jefferson Brain Research Centre, The Manchester Academic Health Science Centre, Northern Care Alliance and The University of Manchester, Manchester, UK
- Division of Neuroscience, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
| | - Tracy A Briggs
- Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK
- Department of Genomic Medicine, St Marys Hospital, Manchester Foundation Trust, Manchester, UK
- Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
| | - Gloria López-Castejón
- Lydia Becker Institute of Immunology and Inflammation, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK
- School of Biological Sciences, Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
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Qin D, Wang C, Yan R, Qin Y, Ying Z, Kong H, Zhao W, Zhang L, Song H. ZAP facilitates NLRP3 inflammasome activation via promoting the oligomerization of NLRP3. Int Immunopharmacol 2024; 133:112123. [PMID: 38663314 DOI: 10.1016/j.intimp.2024.112123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Revised: 04/08/2024] [Accepted: 04/17/2024] [Indexed: 05/12/2024]
Abstract
The NOD-like receptor family protein 3 (NLRP3) inflammasome is a crucial complex for the host to establish inflammatory immune responses and plays vital roles in a series of disorders, including Alzheimer's disease and acute peritonitis. However, its regulatory mechanism remains largely unclear. Zinc finger antiviral protein (ZAP), also known as zinc finger CCCH-type antiviral protein 1 (ZC3HAV1), promotes viral RNA degradation and plays vital roles in host antiviral immune responses. However, the role of ZAP in inflammation, especially in NLRP3 activation, is unclear. Here, we show that ZAP interacts with NLRP3 and promotes NLRP3 oligomerization, thus facilitating NLRP3 inflammasome activation in peritoneal macrophages of C57BL/6 mice. The shorter isoform of ZAP (ZAPS) appears to play a greater role than the full-length isoform (ZAPL) in HEK293T cells. Congruously, Zap-deficient C57BL/6 mice may be less susceptible to alum-induced peritonitis and lipopolysaccharide-induced sepsis in vivo. Therefore, we propose that ZAP is a positive regulator of NLRP3 activation and a potential therapeutic target for NLRP3-related inflammatory disorders.
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Affiliation(s)
- Danhui Qin
- Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, and Key Laboratory of Infection and Immunity of Shandong Province, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China; Department of Pathogenic Biology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Caiwei Wang
- Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, and Key Laboratory of Infection and Immunity of Shandong Province, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China; Department of Pathogenic Biology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Rongzhen Yan
- Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, and Key Laboratory of Infection and Immunity of Shandong Province, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China; Department of Pathogenic Biology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Ying Qin
- Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, and Key Laboratory of Infection and Immunity of Shandong Province, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China; Department of Physiology & Pathophysiology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Zhendong Ying
- Department of Orthopedic Surgery, the First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Jinan, Shandong, China
| | - Hongyi Kong
- Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, and Key Laboratory of Infection and Immunity of Shandong Province, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China; Department of Pathogenic Biology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Wei Zhao
- Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, and Key Laboratory of Infection and Immunity of Shandong Province, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China; Department of Pathogenic Biology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Lei Zhang
- Department of Orthopedic Surgery, the First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Jinan, Shandong, China.
| | - Hui Song
- Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, and Key Laboratory of Infection and Immunity of Shandong Province, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China; Department of Pathogenic Biology, School of Basic Medical Science, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
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王 楠, 谢 咏, 汪 志. [Two Cases of Behcet's Disease-Like Syndrome with Gene Deficiency in ELF4]. SICHUAN DA XUE XUE BAO. YI XUE BAN = JOURNAL OF SICHUAN UNIVERSITY. MEDICAL SCIENCE EDITION 2024; 55:756-761. [PMID: 38948265 PMCID: PMC11211776 DOI: 10.12182/20240560606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Indexed: 07/02/2024]
Abstract
The patient 1, a 13-year-old boy, was admitted due to "recurrent oral ulcers for 3 years, abdominal pain for 8 months, and perianal ulcers for 10 days"; The patient 2, a 3-year-old boy, was admitted due to "recurrent abdominal pain, diarrhea, and fever for over 3 months". Genetic testing of both patients revealed "deficiency in ELF4, X-linked" (DEX), and the patients were diagnosed with Behcet's disease-like syndrome due to deficiency in ELF4, accordingly. The patient 1 was successively given intravenous methylprednisolone pulses and oral prednisone and mesalazine for symptomatic treatment. The patient 2 was successively treated with corticosteroids combined with enteral nutrition, as well as oral mercaptopurine. Subsequently, both patients showed improvements in symptoms and were discharged.
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Affiliation(s)
- 楠 王
- 四川大学华西第二医院 儿科 (成都 610041)Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, China
- 出生缺陷与相关妇儿疾病教育部重点实验室(四川大学) (成都 610041)Key Laboratory of Birth Defects and Related Diseases of Women and Children of the Ministry of Education, Sichuan University, Chengdu 610041, China
- 四川大学华西临床医学院 (成都 610041)West China College of Clinical Medicine, Sichuan University, Chengdu 610041, China
| | - 咏梅 谢
- 四川大学华西第二医院 儿科 (成都 610041)Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, China
- 出生缺陷与相关妇儿疾病教育部重点实验室(四川大学) (成都 610041)Key Laboratory of Birth Defects and Related Diseases of Women and Children of the Ministry of Education, Sichuan University, Chengdu 610041, China
| | - 志凌 汪
- 四川大学华西第二医院 儿科 (成都 610041)Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu 610041, China
- 出生缺陷与相关妇儿疾病教育部重点实验室(四川大学) (成都 610041)Key Laboratory of Birth Defects and Related Diseases of Women and Children of the Ministry of Education, Sichuan University, Chengdu 610041, China
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Wu J, Sun X, Jiang P. Metabolism-inflammasome crosstalk shapes innate and adaptive immunity. Cell Chem Biol 2024; 31:884-903. [PMID: 38759617 DOI: 10.1016/j.chembiol.2024.04.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 04/08/2024] [Accepted: 04/16/2024] [Indexed: 05/19/2024]
Abstract
Inflammasomes are a central component of innate immunity and play a vital role in regulating innate immune response. Activation of inflammasomes is also indispensable for adaptive immunity, modulating the development and response of adaptive immunity. Recently, increasing studies have shown that metabolic alterations and adaptations strongly influence and regulate the differentiation and function of the immune system. In this review, we will take a holistic view of how inflammasomes bridge innate and adaptive (especially T cell) immunity and how inflammasomes crosstalk with metabolic signals during the immune responses. And, special attention will be paid to the metabolic control of inflammasome-mediated interactions between innate and adaptive immunity in disease. Understanding the metabolic regulatory functions of inflammasomes would provide new insights into future research directions in this area and may help to identify potential targets for inflammasome-associated diseases and broaden therapeutic avenues.
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Affiliation(s)
- Jun Wu
- School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, Fujian, China; State Key Laboratory of Molecular Oncology, School of Life Sciences, Tsinghua University, Beijing 100084, China; Tsinghua-Peking Center for Life Sciences, Beijing 100084, China
| | - Xuan Sun
- State Key Laboratory of Molecular Oncology, School of Life Sciences, Tsinghua University, Beijing 100084, China; Tsinghua-Peking Center for Life Sciences, Beijing 100084, China
| | - Peng Jiang
- State Key Laboratory of Molecular Oncology, School of Life Sciences, Tsinghua University, Beijing 100084, China; Tsinghua-Peking Center for Life Sciences, Beijing 100084, China.
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Li SZ, Shu QP, Zhou HM, Liu YY, Fan MQ, Liang XY, Qi LZ, He YN, Liu XY, Du XH, Huang XC, Chen YZ, Du RL, Liang YX, Zhang XD. CLK2 mediates IκBα-independent early termination of NF-κB activation by inducing cytoplasmic redistribution and degradation. Nat Commun 2024; 15:3901. [PMID: 38724505 PMCID: PMC11082251 DOI: 10.1038/s41467-024-48288-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2023] [Accepted: 04/26/2024] [Indexed: 05/12/2024] Open
Abstract
Activation of the NF-κB pathway is strictly regulated to prevent excessive inflammatory and immune responses. In a well-known negative feedback model, IκBα-dependent NF-κB termination is a delayed response pattern in the later stage of activation, and the mechanisms mediating the rapid termination of active NF-κB remain unclear. Here, we showed IκBα-independent rapid termination of nuclear NF-κB mediated by CLK2, which negatively regulated active NF-κB by phosphorylating the RelA/p65 subunit of NF-κB at Ser180 in the nucleus to limit its transcriptional activation through degradation and nuclear export. Depletion of CLK2 increased the production of inflammatory cytokines, reduced viral replication and increased the survival of the mice. Mechanistically, CLK2 phosphorylated RelA/p65 at Ser180 in the nucleus, leading to ubiquitin‒proteasome-mediated degradation and cytoplasmic redistribution. Importantly, a CLK2 inhibitor promoted cytokine production, reduced viral replication, and accelerated murine psoriasis. This study revealed an IκBα-independent mechanism of early-stage termination of NF-κB in which phosphorylated Ser180 RelA/p65 turned off posttranslational modifications associated with transcriptional activation, ultimately resulting in the degradation and nuclear export of RelA/p65 to inhibit excessive inflammatory activation. Our findings showed that the phosphorylation of RelA/p65 at Ser180 in the nucleus inhibits early-stage NF-κB activation, thereby mediating the negative regulation of NF-κB.
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Affiliation(s)
- Shang-Ze Li
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072, Hubei, China
- School of Medicine, Chongqing University, Chongqing, 400044, China
| | - Qi-Peng Shu
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072, Hubei, China
| | - Hai-Meng Zhou
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072, Hubei, China
| | - Yu-Ying Liu
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072, Hubei, China
| | - Meng-Qi Fan
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072, Hubei, China
| | - Xin-Yi Liang
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072, Hubei, China
| | - Lin-Zhi Qi
- School of Medicine, Chongqing University, Chongqing, 400044, China
| | - Ya-Nan He
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072, Hubei, China
| | - Xue-Yi Liu
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072, Hubei, China
| | - Xue-Hua Du
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072, Hubei, China
| | - Xi-Chen Huang
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072, Hubei, China
| | - Yu-Zhen Chen
- Key Laboratory of Research on Clinical Molecular Diagnosis for High Incidence Diseases in Western Guangxi of Guangxi Higher Education Institutions & Department of Gynecology, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China
| | - Run-Lei Du
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072, Hubei, China.
| | - Yue-Xiu Liang
- Key Laboratory of Research on Clinical Molecular Diagnosis for High Incidence Diseases in Western Guangxi of Guangxi Higher Education Institutions & Department of Gynecology, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China.
| | - Xiao-Dong Zhang
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan, 430072, Hubei, China.
- Key Laboratory of Research on Clinical Molecular Diagnosis for High Incidence Diseases in Western Guangxi of Guangxi Higher Education Institutions & Department of Gynecology, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China.
- National Health Commission Key Laboratory of Birth Defect Research and Prevention & MOE Key Lab of Rare Pediatric Diseases, Department of Cell Biology and Genetics, School of Basic Medical Sciences, Hengyang Medical School, University of South China, Hengyang, China.
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Everson RG, Hugo W, Sun L, Antonios J, Lee A, Ding L, Bu M, Khattab S, Chavez C, Billingslea-Yoon E, Salazar A, Ellingson BM, Cloughesy TF, Liau LM, Prins RM. TLR agonists polarize interferon responses in conjunction with dendritic cell vaccination in malignant glioma: a randomized phase II Trial. Nat Commun 2024; 15:3882. [PMID: 38719809 PMCID: PMC11078958 DOI: 10.1038/s41467-024-48073-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Accepted: 04/19/2024] [Indexed: 05/12/2024] Open
Abstract
In this randomized phase II clinical trial, we evaluated the effectiveness of adding the TLR agonists, poly-ICLC or resiquimod, to autologous tumor lysate-pulsed dendritic cell (ATL-DC) vaccination in patients with newly-diagnosed or recurrent WHO Grade III-IV malignant gliomas. The primary endpoints were to assess the most effective combination of vaccine and adjuvant in order to enhance the immune potency, along with safety. The combination of ATL-DC vaccination and TLR agonist was safe and found to enhance systemic immune responses, as indicated by increased interferon gene expression and changes in immune cell activation. Specifically, PD-1 expression increases on CD4+ T-cells, while CD38 and CD39 expression are reduced on CD8+ T cells, alongside an increase in monocytes. Poly-ICLC treatment amplifies the induction of interferon-induced genes in monocytes and T lymphocytes. Patients that exhibit higher interferon response gene expression demonstrate prolonged survival and delayed disease progression. These findings suggest that combining ATL-DC with poly-ICLC can induce a polarized interferon response in circulating monocytes and CD8+ T cells, which may represent an important blood biomarker for immunotherapy in this patient population.Trial Registration: ClinicalTrials.gov Identifier: NCT01204684.
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Affiliation(s)
- Richard G Everson
- Department of Neurosurgery, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA
- Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA
| | - Willy Hugo
- Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA
- Department of Medicine, Division of Dermatology, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA
- Parker Institute for Cancer Immunotherapy, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA
| | - Lu Sun
- Department of Neurosurgery, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA
| | - Joseph Antonios
- Department of Neurosurgery, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA
| | - Alexander Lee
- Department of Neurosurgery, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA
| | - Lizhong Ding
- Department of Medicine, Division of Dermatology, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA
| | - Melissa Bu
- Department of Medicine, Division of Dermatology, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA
| | - Sara Khattab
- Department of Neurosurgery, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA
| | - Carolina Chavez
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA
| | - Emma Billingslea-Yoon
- Department of Neurosurgery, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA
| | | | - Benjamin M Ellingson
- Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA
- Department of Radiological Sciences, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA
| | - Timothy F Cloughesy
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA
- Department of Neurology/Neuro-Oncology, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA
| | - Linda M Liau
- Department of Neurosurgery, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA.
- Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA.
| | - Robert M Prins
- Department of Neurosurgery, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA.
- Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA.
- Parker Institute for Cancer Immunotherapy, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA.
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, CA, 90095, USA.
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Feng J, Liu Y, Kim J, Ahangari F, Kaminski N, Bain WG, Jie Z, Dela Cruz CS, Sharma L. Anti-inflammatory roles of type I interferon signaling in the lung. Am J Physiol Lung Cell Mol Physiol 2024; 326:L551-L561. [PMID: 38375579 PMCID: PMC11380987 DOI: 10.1152/ajplung.00353.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Revised: 01/23/2024] [Accepted: 02/09/2024] [Indexed: 02/21/2024] Open
Abstract
Excessive or persistent inflammation may have detrimental effects on lung structure and function. Currently, our understanding of conserved host mechanisms that control the inflammatory response remains incompletely understood. In this study, we investigated the role of type I interferon signaling in the inflammatory response against diverse clinically relevant stimuli. Using mice deficient in type I interferon signaling (IFNAR1-/-), we demonstrate that the absence of interferon signaling resulted in a robust and persistent inflammatory response against Pseudomonas aeruginosa, lipopolysaccharide, and chemotherapeutic agent bleomycin. The elevated inflammatory response in IFNAR1-/- mice was manifested as elevated myeloid cells, such as macrophages and neutrophils, in the bronchoalveolar lavage. The inflammatory cell response in the IFNAR1-/- mice persisted to 14 days and there is impaired recovery and fibrotic remodeling of the lung in IFNAR1-/- mice after bleomycin injury. In the Pseudomonas infection model, the elevated inflammatory cell response led to improved bacterial clearance in IFNAR1-/- mice, although there was similar lung injury and survival. We performed RNA sequencing of lung tissue in wild-type and IFNAR1-/- mice after LPS and bleomycin injury. Our unbiased analysis identified differentially expressed genes between IFNAR1-/- and wild-type mice, including previously unknown regulation of nucleotide-binding oligomerization domain (NOD)-like receptor signaling, retinoic acid-inducible gene-I (RIG-I) signaling, and necroptosis pathway by type I interferon signaling in both models. These data provide novel insights into the conserved anti-inflammatory mechanisms of the type I interferon signaling.NEW & NOTEWORTHY Type I interferons are known for their antiviral activities. In this study, we demonstrate a conserved anti-inflammatory role of type I interferon signaling against diverse stimuli in the lung. We show that exacerbated inflammatory response in the absence of type I interferon signaling has both acute and chronic consequences in the lung including structural changes.
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Affiliation(s)
- Jingjing Feng
- Department of Pulmonary and Critical Care Medicine, Shanghai Fifth People's Hospital, Center of Community-Based Health Research, Fudan University, Shanghai, China
- Section of Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut, United States
| | - Yi Liu
- Shanghai Emerging and Re-emerging Institute, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Jooyoung Kim
- Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
| | - Farida Ahangari
- Section of Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut, United States
| | - Naftali Kaminski
- Section of Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut, United States
| | - William G Bain
- Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
- Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania, United States
| | - Zhijun Jie
- Department of Pulmonary and Critical Care Medicine, Shanghai Fifth People's Hospital, Center of Community-Based Health Research, Fudan University, Shanghai, China
| | - Charles S Dela Cruz
- Section of Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut, United States
- Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
- Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania, United States
| | - Lokesh Sharma
- Section of Pulmonary, Critical Care and Sleep Medicine, Yale School of Medicine, New Haven, Connecticut, United States
- Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States
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Neamțu M, Bild V, Vasincu A, Arcan OD, Bulea D, Ababei DC, Rusu RN, Macadan I, Sciucă AM, Neamțu A. Inflammasome Molecular Insights in Autoimmune Diseases. Curr Issues Mol Biol 2024; 46:3502-3532. [PMID: 38666950 PMCID: PMC11048795 DOI: 10.3390/cimb46040220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 04/15/2024] [Accepted: 04/16/2024] [Indexed: 04/28/2024] Open
Abstract
Autoimmune diseases (AIDs) emerge due to an irregular immune response towards self- and non-self-antigens. Inflammation commonly accompanies these conditions, with inflammatory factors and inflammasomes playing pivotal roles in their progression. Key concepts in molecular biology, inflammation, and molecular mimicry are crucial to understanding AID development. Exposure to foreign antigens can cause inflammation, potentially leading to AIDs through molecular mimicry triggered by cross-reactive epitopes. Molecular mimicry emerges as a key mechanism by which infectious or chemical agents trigger autoimmunity. In certain susceptible individuals, autoreactive T or B cells may be activated by a foreign antigen due to resemblances between foreign and self-peptides. Chronic inflammation, typically driven by abnormal immune responses, is strongly associated with AID pathogenesis. Inflammasomes, which are vital cytosolic multiprotein complexes assembled in response to infections and stress, are crucial to activating inflammatory processes in macrophages. Chronic inflammation, characterized by prolonged tissue injury and repair cycles, can significantly damage tissues, thereby increasing the risk of AIDs. Inhibiting inflammasomes, particularly in autoinflammatory disorders, has garnered significant interest, with pharmaceutical advancements targeting cytokines and inflammasomes showing promise in AID management.
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Affiliation(s)
- Monica Neamțu
- Department of Pharmacodynamics and Clinical Pharmacy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania; (M.N.); (V.B.); (O.D.A.); (D.B.); (D.-C.A.); (R.-N.R.); (I.M.)
| | - Veronica Bild
- Department of Pharmacodynamics and Clinical Pharmacy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania; (M.N.); (V.B.); (O.D.A.); (D.B.); (D.-C.A.); (R.-N.R.); (I.M.)
- Center of Biomedical Research of the Romanian Academy, 8 Carol I Avenue, 700506 Iasi, Romania
| | - Alexandru Vasincu
- Department of Pharmacodynamics and Clinical Pharmacy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania; (M.N.); (V.B.); (O.D.A.); (D.B.); (D.-C.A.); (R.-N.R.); (I.M.)
| | - Oana Dana Arcan
- Department of Pharmacodynamics and Clinical Pharmacy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania; (M.N.); (V.B.); (O.D.A.); (D.B.); (D.-C.A.); (R.-N.R.); (I.M.)
| | - Delia Bulea
- Department of Pharmacodynamics and Clinical Pharmacy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania; (M.N.); (V.B.); (O.D.A.); (D.B.); (D.-C.A.); (R.-N.R.); (I.M.)
| | - Daniela-Carmen Ababei
- Department of Pharmacodynamics and Clinical Pharmacy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania; (M.N.); (V.B.); (O.D.A.); (D.B.); (D.-C.A.); (R.-N.R.); (I.M.)
| | - Răzvan-Nicolae Rusu
- Department of Pharmacodynamics and Clinical Pharmacy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania; (M.N.); (V.B.); (O.D.A.); (D.B.); (D.-C.A.); (R.-N.R.); (I.M.)
| | - Ioana Macadan
- Department of Pharmacodynamics and Clinical Pharmacy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania; (M.N.); (V.B.); (O.D.A.); (D.B.); (D.-C.A.); (R.-N.R.); (I.M.)
| | - Ana Maria Sciucă
- Department of Oral Medicine, Oral Dermatology, “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania
| | - Andrei Neamțu
- Department of Physiology, “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universitatii Street, 700115 Iasi, Romania;
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Abstract
Vascular disease is a major cause of morbidity and mortality in patients with systemic autoimmune diseases, particularly systemic lupus erythematosus (SLE). Although comorbid cardiovascular risk factors are frequently present in patients with SLE, they do not explain the high burden of premature vascular disease. Profound innate and adaptive immune dysregulation seems to be the primary driver of accelerated vascular damage in SLE. In particular, evidence suggests that dysregulation of type 1 interferon (IFN-I) and aberrant neutrophils have key roles in the pathogenesis of vascular damage. IFN-I promotes endothelial dysfunction directly via effects on endothelial cells and indirectly via priming of immune cells that contribute to vascular damage. SLE neutrophils are vasculopathic in part because of their increased ability to form immunostimulatory neutrophil extracellular traps. Despite improvements in clinical care, cardiovascular disease remains the leading cause of mortality among patients with SLE, and treatments that improve vascular outcomes are urgently needed. Improved understanding of the mechanisms of vascular injury in inflammatory conditions such as SLE could also have implications for common cardiovascular diseases, such as atherosclerosis and hypertension, and may ultimately lead to personalized therapeutic approaches to the prevention and treatment of this potentially fatal complication.
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Affiliation(s)
- William G Ambler
- Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Mariana J Kaplan
- Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA.
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Zhang XJ, Wang Z, Chen JW, Yuan SY, Zhao L, Zhong JY, Chen JJ, Lin WJ, Wu WS. The neuroprotective effect of near infrared light therapy in aged mice with postoperative neurocognitive disorder by upregulating IRF7. J Affect Disord 2024; 349:297-309. [PMID: 38211750 DOI: 10.1016/j.jad.2024.01.074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 12/24/2023] [Accepted: 01/04/2024] [Indexed: 01/13/2024]
Abstract
BACKGROUND Postoperative neurocognitive disorder (PND) is a common central nervous system complication after undergoing surgery and anesthesia especially in elderly patients, while the therapeutic options are very limited. This study was carried out to investigate the beneficial effects of transcranial near infrared light (NIRL) which was employed to the treatment of PND and propose the involved mechanisms. METHODS The PND mice were established through left carotid artery exposure under isoflurane anesthesia and received transcranial NIRL treatment. Behavioral testing was performed to evaluate the cognitive function of PND mice after transcranial NIRL therapy. Changes in the transcriptomic profiles of prefrontal cortex (PFC) and hippocampus (HP) were identified by next generation sequencing (NGS), and the molecular mechanisms involved were examined by both in vivo mouse model and in vitro cell culture studies. RESULTS We found that transcranial NIRL therapy effectively ameliorated learning and memory deficit induced by anesthesia and surgery in aged mice. Specifically, we identified down-regulation of interferon regulatory factor 7 (IRF7) in the brains of PND mice that was mechanistically associated with increased pro-inflammatory M1 phenotype of microglia and elevated neuroinflammatory. NIRL treatment produced protective effects through the upregulation of IRF7 expression and reversing microglial phenotypes from pro-inflammatory to neuroprotective, resulting in reduced brain damage and improved cognitive function in PND mice. CONCLUSION Our results indicate that transcranial NIRL is an effective and safe therapy for PND via alleviating neuroinflammation, and IRF7 plays a key transcription factor in regulating the M1-to-M2 switch of microglia.
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Affiliation(s)
- Xiao-Jun Zhang
- Department of Anesthesiology, Qilu Hospital of Shandong University, Jinan, Shandong, China
| | - Zhi Wang
- Department of Anesthesiology, Sun Yat-Sen Memorial Hospital, Guangzhou, China
| | - Jia-Wei Chen
- Department of Anesthesiology, Sun Yat-Sen Memorial Hospital, Guangzhou, China
| | - Shang-Yan Yuan
- Department of Anesthesiology, Sun Yat-Sen Memorial Hospital, Guangzhou, China
| | - Le Zhao
- Department of Anesthesiology, Sun Yat-Sen Memorial Hospital, Guangzhou, China
| | - Jun-Ying Zhong
- Department of Anesthesiology, Sun Yat-Sen Memorial Hospital, Guangzhou, China
| | - Jun-Jun Chen
- Department of Anesthesiology, Sun Yat-Sen Memorial Hospital, Guangzhou, China
| | - Wei-Jye Lin
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China; Medical Research Center of Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Wen-Si Wu
- Department of Thoracic Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China.
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Suresh Kumar Meena Kumari M, Liu P, Jump K, Morales Y, Miller EA, Shecter I, Stadecker MJ, Kalantari P. NLRP3 and AIM2 inflammasomes exacerbate the pathogenic Th17 cell response to eggs of the helminth Schistosoma mansoni. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.03.11.584371. [PMID: 38559160 PMCID: PMC10979858 DOI: 10.1101/2024.03.11.584371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 04/04/2024]
Abstract
Infection with the helminth Schistosoma mansoni can cause exacerbated morbidity and mortality via a pathogenic host CD4 T cell-mediated immune response directed against parasite egg antigens, with T helper (Th) 17 cells playing a major role in the development of severe granulomatous hepatic immunopathology. The role of inflammasomes in intensifying disease has been reported; however, neither the types of caspases and inflammasomes involved, nor their impact on the Th17 response are known. Here we show that enhanced egg-induced IL-1β secretion and pyroptotic cell death required both caspase-1 and caspase-8 as well as NLRP3 and AIM2 inflammasome activation. Schistosome genomic DNA activated AIM2, whereas reactive oxygen species, potassium efflux and cathepsin B, were the major activators of NLRP3. NLRP3 and AIM2 deficiency led to a significant reduction in pathogenic Th17 responses, suggesting their crucial and non-redundant role in promoting inflammation. Additionally, we show that NLRP3- and AIM2-induced IL-1β suppressed IL-4 and protective Type I IFN (IFN-I) production, which further enhanced inflammation. IFN-I signaling also curbed inflammasome- mediated IL-1β production suggesting that these two antagonistic pathways shape the severity of disease. Lastly, Gasdermin D (Gsdmd) deficiency resulted in a marked decrease in egg-induced granulomatous inflammation. Our findings establish NLRP3/AIM2-Gsdmd axis as a central inducer of pathogenic Th17 responses which is counteracted by IFN-I pathway in schistosomiasis.
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Affiliation(s)
- Madhusoodhanan Suresh Kumar Meena Kumari
- Department of Veterinary and Biomedical Sciences, Center for Molecular Immunology and Infectious Disease, Pennsylvania State University, University Park, Pennsylvania, United States of America
| | - Pengyu Liu
- Department of Veterinary and Biomedical Sciences, Center for Molecular Immunology and Infectious Disease, Pennsylvania State University, University Park, Pennsylvania, United States of America
| | - Kaile Jump
- Department of Veterinary and Biomedical Sciences, Center for Molecular Immunology and Infectious Disease, Pennsylvania State University, University Park, Pennsylvania, United States of America
| | - Yoelkys Morales
- Department of Immunology, Tufts University School of Medicine, Boston, Massachusetts, United States of America
| | - Emily A Miller
- Department of Immunology, Tufts University School of Medicine, Boston, Massachusetts, United States of America
| | - Ilana Shecter
- Department of Immunology, Tufts University School of Medicine, Boston, Massachusetts, United States of America
| | - Miguel J. Stadecker
- Department of Immunology, Tufts University School of Medicine, Boston, Massachusetts, United States of America
| | - Parisa Kalantari
- Department of Veterinary and Biomedical Sciences, Center for Molecular Immunology and Infectious Disease, Pennsylvania State University, University Park, Pennsylvania, United States of America
- Department of Immunology, Tufts University School of Medicine, Boston, Massachusetts, United States of America
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46
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Minayoshi Y, Maeda H, Hamasaki K, Nagasaki T, Takano M, Fukuda R, Mizuta Y, Tanaka M, Sasaki Y, Otagiri M, Watanabe H, Maruyama T. Mouse Type-I Interferon-Mannosylated Albumin Fusion Protein for the Treatment of Chronic Hepatitis. Pharmaceuticals (Basel) 2024; 17:260. [PMID: 38399475 PMCID: PMC10893114 DOI: 10.3390/ph17020260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Revised: 02/03/2024] [Accepted: 02/07/2024] [Indexed: 02/25/2024] Open
Abstract
Although a lot of effort has been put into creating drugs and combination therapies against chronic hepatitis, no effective treatment has been established. Type-I interferon is a promising therapeutic for chronic hepatitis due to its excellent anti-inflammatory effects through interferon receptors on hepatic macrophages. To develop a type-I IFN equipped with the ability to target hepatic macrophages through the macrophage mannose receptor, the present study designed a mouse type-I interferon-mannosylated albumin fusion protein using site-specific mutagenesis and albumin fusion technology. This fusion protein exhibited the induction of anti-inflammatory molecules, such as IL-10, IL-1Ra, and PD-1, in RAW264.7 cells, or hepatoprotective effects on carbon tetrachloride-induced chronic hepatitis mice. As expected, such biological and hepatoprotective actions were significantly superior to those of human fusion proteins. Furthermore, the repeated administration of mouse fusion protein to carbon tetrachloride-induced chronic hepatitis mice clearly suppressed the area of liver fibrosis and hepatic hydroxyproline contents, not only with a reduction in the levels of inflammatory cytokine (TNF-α) and fibrosis-related genes (TGF-β, Fibronectin, Snail, and Collagen 1α2), but also with a shift in the hepatic macrophage phenotype from inflammatory to anti-inflammatory. Therefore, type-I interferon-mannosylated albumin fusion protein has the potential as a new therapeutic agent for chronic hepatitis.
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Affiliation(s)
- Yuki Minayoshi
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto 862-0973, Japan; (Y.M.); (K.H.); (T.N.); (M.T.); (R.F.); (Y.M.); (H.W.)
| | - Hitoshi Maeda
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto 862-0973, Japan; (Y.M.); (K.H.); (T.N.); (M.T.); (R.F.); (Y.M.); (H.W.)
| | - Keisuke Hamasaki
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto 862-0973, Japan; (Y.M.); (K.H.); (T.N.); (M.T.); (R.F.); (Y.M.); (H.W.)
| | - Taisei Nagasaki
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto 862-0973, Japan; (Y.M.); (K.H.); (T.N.); (M.T.); (R.F.); (Y.M.); (H.W.)
| | - Mei Takano
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto 862-0973, Japan; (Y.M.); (K.H.); (T.N.); (M.T.); (R.F.); (Y.M.); (H.W.)
| | - Ryo Fukuda
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto 862-0973, Japan; (Y.M.); (K.H.); (T.N.); (M.T.); (R.F.); (Y.M.); (H.W.)
| | - Yuki Mizuta
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto 862-0973, Japan; (Y.M.); (K.H.); (T.N.); (M.T.); (R.F.); (Y.M.); (H.W.)
| | - Motohiko Tanaka
- Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan; (M.T.); (Y.S.)
- Public Health and Welfare Bureau, 5-1-1 Oe, Chuo-ku, Kumamoto 862-0971, Japan
| | - Yutaka Sasaki
- Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto 860-8556, Japan; (M.T.); (Y.S.)
- Osaka Central Hospital, 3-3-30 Umeda, Kita-ku, Osaka 530-0001, Japan
| | - Masaki Otagiri
- Faculty of Pharmaceutical Sciences, Sojo University, 4-22-1 Ikeda, Nishi-ku, Kumamoto 860-0082, Japan;
- DDS Research Institute, Sojo University, 4-22-1 Ikeda, Nishi-ku, Kumamoto 860-0082, Japan
| | - Hiroshi Watanabe
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto 862-0973, Japan; (Y.M.); (K.H.); (T.N.); (M.T.); (R.F.); (Y.M.); (H.W.)
| | - Toru Maruyama
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, Chuo-ku, Kumamoto 862-0973, Japan; (Y.M.); (K.H.); (T.N.); (M.T.); (R.F.); (Y.M.); (H.W.)
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Stergiou IE, Tsironis C, Papadakos SP, Tsitsilonis OE, Dimopoulos MA, Theocharis S. Unraveling the Role of the NLRP3 Inflammasome in Lymphoma: Implications in Pathogenesis and Therapeutic Strategies. Int J Mol Sci 2024; 25:2369. [PMID: 38397043 PMCID: PMC10889189 DOI: 10.3390/ijms25042369] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 02/10/2024] [Accepted: 02/13/2024] [Indexed: 02/25/2024] Open
Abstract
Inflammasomes are multimeric protein complexes, sensors of intracellular danger signals, and crucial components of the innate immune system, with the NLRP3 inflammasome being the best characterized among them. The increasing scientific interest in the mechanisms interconnecting inflammation and tumorigenesis has led to the study of the NLRP3 inflammasome in the setting of various neoplasms. Despite a plethora of data regarding solid tumors, NLRP3 inflammasome's implication in the pathogenesis of hematological malignancies only recently gained attention. In this review, we investigate its role in normal lymphopoiesis and lymphomagenesis. Considering that lymphomas comprise a heterogeneous group of hematologic neoplasms, both tumor-promoting and tumor-suppressing properties were attributed to the NLRP3 inflammasome, affecting neoplastic cells and immune cells in the tumor microenvironment. NLRP3 inflammasome-related proteins were associated with disease characteristics, response to treatment, and prognosis. Few studies assess the efficacy of NLRP3 inflammasome therapeutic targeting with encouraging results, though most are still at the preclinical level. Further understanding of the mechanisms regulating NLRP3 inflammasome activation during lymphoma development and progression can contribute to the investigation of novel treatment approaches to cover unmet needs in lymphoma therapeutics.
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Affiliation(s)
- Ioanna E. Stergiou
- Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (I.E.S.); (C.T.)
| | - Christos Tsironis
- Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (I.E.S.); (C.T.)
| | - Stavros P. Papadakos
- First Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, 10679 Athens, Greece;
| | - Ourania E. Tsitsilonis
- Flow Cytometry Unit, Department of Biology, School of Science, National and Kapodistrian University of Athens, 15784 Athens, Greece;
| | - Meletios Athanasios Dimopoulos
- Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Alexandra Hospital, 11528 Athens, Greece;
| | - Stamatios Theocharis
- First Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, 10679 Athens, Greece;
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Toribio-Fernández R, Tristão-Pereira C, Carlos Silla-Castro J, Callejas S, Oliva B, Fernandez-Nueda I, Garcia-Lunar I, Perez-Herreras C, María Ordovás J, Martin P, Blanco-Kelly F, Ayuso C, Lara-Pezzi E, Fernandez-Ortiz A, Garcia-Alvarez A, Dopazo A, Sanchez-Cabo F, Ibanez B, Cortes-Canteli M, Fuster V. Apolipoprotein E-ε2 and Resistance to Atherosclerosis in Midlife: The PESA Observational Study. Circ Res 2024; 134:411-424. [PMID: 38258600 DOI: 10.1161/circresaha.123.323921] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Accepted: 01/10/2024] [Indexed: 01/24/2024]
Abstract
BACKGROUND APOE is a known genetic contributor to cardiovascular disease, but the differential role APOE alleles play in subclinical atherosclerosis remains unclear. METHODS The PESA (Progression of Early Subclinical Atherosclerosis) is an observational cohort study that recruited 4184 middle-aged asymptomatic individuals to be screened for cardiovascular risk and multiterritorial subclinical atherosclerosis. Participants were APOE-genotyped, and omics data were additionally evaluated. RESULTS In the PESA study, the frequencies for APOE -ε2, -ε3, and -ε4 alleles were 0.060, 0.844, and 0.096, respectively. This study included a subcohort of 3887 participants (45.8±4.3 years of age; 62% males). As expected, APOE-ε4 carriers were at the highest risk for cardiovascular disease and had significantly greater odds of having subclinical atherosclerosis compared with ε3/ε3 carriers, which was mainly explained by their higher levels of low-density lipoprotein (LDL)-cholesterol. In turn, APOE-ε2 carriers were at the lowest risk for cardiovascular disease and had significantly lower odds of having subclinical atherosclerosis in several vascular territories (carotids: 0.62 [95% CI, 0.47-0.81]; P=0.00043; femorals: 0.60 [0.47-0.78]; P=9.96×10-5; coronaries: 0.53 [0.39-0.74]; P=0.00013; and increased PESA score: 0.58 [0.48-0.71]; P=3.16×10-8). This APOE-ε2 atheroprotective effect was mostly independent of the associated lower LDL-cholesterol levels and other cardiovascular risk factors. The protection conferred by the ε2 allele was greater with age (50-54 years: 0.49 [95% CI, 0.32-0.73]; P=0.00045), and normal (<150 mg/dL) levels of triglycerides (0.54 [0.44-0.66]; P=4.70×10-9 versus 0.90 [0.57-1.43]; P=0.67 if ≥150 mg/dL). Omics analysis revealed an enrichment of several canonical pathways associated with anti-inflammatory mechanisms together with the modulation of erythrocyte homeostasis, coagulation, and complement activation in ε2 carriers that might play a relevant role in the ε2's atheroprotective effect. CONCLUSIONS This work sheds light on the role of APOE in cardiovascular disease development with important therapeutic and prevention implications on cardiovascular health, especially in early midlife. REGISTRATION URL: https://www.clinicaltrials.gov: NCT01410318.
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Affiliation(s)
- Raquel Toribio-Fernández
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain (R.T.-F., C.T.-P., J.C.S.-C., S.C., B.O., I.F.-N., I.G.-L., J.M.O., P.M., E.L.-P., A.F.-O., A.G.-A., A.D., F.S.-C., B.I., M.C.-C., V.F.)
- Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD), Madrid, Spain (R.T.-F., F.B.-K., C.A., B.I., M.C.-C.)
| | - Catarina Tristão-Pereira
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain (R.T.-F., C.T.-P., J.C.S.-C., S.C., B.O., I.F.-N., I.G.-L., J.M.O., P.M., E.L.-P., A.F.-O., A.G.-A., A.D., F.S.-C., B.I., M.C.-C., V.F.)
| | - Juan Carlos Silla-Castro
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain (R.T.-F., C.T.-P., J.C.S.-C., S.C., B.O., I.F.-N., I.G.-L., J.M.O., P.M., E.L.-P., A.F.-O., A.G.-A., A.D., F.S.-C., B.I., M.C.-C., V.F.)
| | - Sergio Callejas
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain (R.T.-F., C.T.-P., J.C.S.-C., S.C., B.O., I.F.-N., I.G.-L., J.M.O., P.M., E.L.-P., A.F.-O., A.G.-A., A.D., F.S.-C., B.I., M.C.-C., V.F.)
| | - Belen Oliva
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain (R.T.-F., C.T.-P., J.C.S.-C., S.C., B.O., I.F.-N., I.G.-L., J.M.O., P.M., E.L.-P., A.F.-O., A.G.-A., A.D., F.S.-C., B.I., M.C.-C., V.F.)
| | - Irene Fernandez-Nueda
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain (R.T.-F., C.T.-P., J.C.S.-C., S.C., B.O., I.F.-N., I.G.-L., J.M.O., P.M., E.L.-P., A.F.-O., A.G.-A., A.D., F.S.-C., B.I., M.C.-C., V.F.)
| | - Ines Garcia-Lunar
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain (R.T.-F., C.T.-P., J.C.S.-C., S.C., B.O., I.F.-N., I.G.-L., J.M.O., P.M., E.L.-P., A.F.-O., A.G.-A., A.D., F.S.-C., B.I., M.C.-C., V.F.)
- Cardiology Department, University Hospital La Moraleja, Madrid, Spain (I.G.-L.)
- CIBER de enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III (ISCIII), Madrid, Spain (I.G.-L., P.M., A.F.-O., A.G.-A., B.I.)
| | | | - José María Ordovás
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain (R.T.-F., C.T.-P., J.C.S.-C., S.C., B.O., I.F.-N., I.G.-L., J.M.O., P.M., E.L.-P., A.F.-O., A.G.-A., A.D., F.S.-C., B.I., M.C.-C., V.F.)
- Precision Nutrition and Obesity Research Program, IMDEA Food Institute, CEI UAM+CSI, Madrid, Spain (J.M.O.)
- U.S. Department of Agriculture Human Nutrition Research Center of Aging, Tufts University, MA (J.M.O.)
| | - Pilar Martin
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain (R.T.-F., C.T.-P., J.C.S.-C., S.C., B.O., I.F.-N., I.G.-L., J.M.O., P.M., E.L.-P., A.F.-O., A.G.-A., A.D., F.S.-C., B.I., M.C.-C., V.F.)
- CIBER de enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III (ISCIII), Madrid, Spain (I.G.-L., P.M., A.F.-O., A.G.-A., B.I.)
| | - Fiona Blanco-Kelly
- Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD), Madrid, Spain (R.T.-F., F.B.-K., C.A., B.I., M.C.-C.)
- CIBER de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain (F.B.-K., C.A.)
| | - Carmen Ayuso
- Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD), Madrid, Spain (R.T.-F., F.B.-K., C.A., B.I., M.C.-C.)
- CIBER de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain (F.B.-K., C.A.)
| | - Enrique Lara-Pezzi
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain (R.T.-F., C.T.-P., J.C.S.-C., S.C., B.O., I.F.-N., I.G.-L., J.M.O., P.M., E.L.-P., A.F.-O., A.G.-A., A.D., F.S.-C., B.I., M.C.-C., V.F.)
| | - Antonio Fernandez-Ortiz
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain (R.T.-F., C.T.-P., J.C.S.-C., S.C., B.O., I.F.-N., I.G.-L., J.M.O., P.M., E.L.-P., A.F.-O., A.G.-A., A.D., F.S.-C., B.I., M.C.-C., V.F.)
- CIBER de enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III (ISCIII), Madrid, Spain (I.G.-L., P.M., A.F.-O., A.G.-A., B.I.)
- Hospital Clínico San Carlos, IdISSC, Universidad Complutense, Madrid, Spain (A.F.-O.)
| | - Ana Garcia-Alvarez
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain (R.T.-F., C.T.-P., J.C.S.-C., S.C., B.O., I.F.-N., I.G.-L., J.M.O., P.M., E.L.-P., A.F.-O., A.G.-A., A.D., F.S.-C., B.I., M.C.-C., V.F.)
- CIBER de enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III (ISCIII), Madrid, Spain (I.G.-L., P.M., A.F.-O., A.G.-A., B.I.)
- Hospital Clínic de Barcelona, IDIBAPS, Universitat de Barcelona, Spain (A.G.-A.)
| | - Ana Dopazo
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain (R.T.-F., C.T.-P., J.C.S.-C., S.C., B.O., I.F.-N., I.G.-L., J.M.O., P.M., E.L.-P., A.F.-O., A.G.-A., A.D., F.S.-C., B.I., M.C.-C., V.F.)
| | - Fatima Sanchez-Cabo
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain (R.T.-F., C.T.-P., J.C.S.-C., S.C., B.O., I.F.-N., I.G.-L., J.M.O., P.M., E.L.-P., A.F.-O., A.G.-A., A.D., F.S.-C., B.I., M.C.-C., V.F.)
| | - Borja Ibanez
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain (R.T.-F., C.T.-P., J.C.S.-C., S.C., B.O., I.F.-N., I.G.-L., J.M.O., P.M., E.L.-P., A.F.-O., A.G.-A., A.D., F.S.-C., B.I., M.C.-C., V.F.)
- Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD), Madrid, Spain (R.T.-F., F.B.-K., C.A., B.I., M.C.-C.)
- CIBER de enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III (ISCIII), Madrid, Spain (I.G.-L., P.M., A.F.-O., A.G.-A., B.I.)
| | - Marta Cortes-Canteli
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain (R.T.-F., C.T.-P., J.C.S.-C., S.C., B.O., I.F.-N., I.G.-L., J.M.O., P.M., E.L.-P., A.F.-O., A.G.-A., A.D., F.S.-C., B.I., M.C.-C., V.F.)
- Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD), Madrid, Spain (R.T.-F., F.B.-K., C.A., B.I., M.C.-C.)
| | - Valentin Fuster
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain (R.T.-F., C.T.-P., J.C.S.-C., S.C., B.O., I.F.-N., I.G.-L., J.M.O., P.M., E.L.-P., A.F.-O., A.G.-A., A.D., F.S.-C., B.I., M.C.-C., V.F.)
- Icahn School of Medicine at Mount Sinai, New York (V.F.)
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Lee J, Ou JHJ. HCV-induced autophagy and innate immunity. Front Immunol 2024; 15:1305157. [PMID: 38370419 PMCID: PMC10874285 DOI: 10.3389/fimmu.2024.1305157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Accepted: 01/19/2024] [Indexed: 02/20/2024] Open
Abstract
The interplay between autophagy and host innate immunity has been of great interest. Hepatitis C virus (HCV) impedes signaling pathways initiated by pattern-recognition receptors (PRRs) that recognize pathogens-associated molecular patterns (PAMPs). Autophagy, a cellular catabolic process, delivers damaged organelles and protein aggregates to lysosomes for degradation and recycling. Autophagy is also an innate immune response of cells to trap pathogens in membrane vesicles for removal. However, HCV controls the autophagic pathway and uses autophagic membranes to enhance its replication. Mitophagy, a selective autophagy targeting mitochondria, alters the dynamics and metabolism of mitochondria, which play important roles in host antiviral responses. HCV also alters mitochondrial dynamics and promotes mitophagy to prevent premature cell death and attenuate the interferon (IFN) response. In addition, the dysregulation of the inflammasomal response by HCV leads to IFN resistance and immune tolerance. These immune evasion properties of HCV allow HCV to successfully replicate and persist in its host cells. In this article, we discuss HCV-induced autophagy/mitophagy and its associated immunological responses and provide a review of our current understanding of how these processes are regulated in HCV-infected cells.
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Affiliation(s)
| | - J.-H. James Ou
- Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, Los Angeles, CA, United States
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50
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Tang J, Gu Y, Wang X, Luo Y, Zhang F, Zheng J, Wang Y, Shen X, Xu L. Salmonella T3SS-elicited inflammatory innate immune response inhibits type I IFN response in macrophages. Vet Microbiol 2024; 289:109970. [PMID: 38154394 DOI: 10.1016/j.vetmic.2023.109970] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Revised: 12/08/2023] [Accepted: 12/21/2023] [Indexed: 12/30/2023]
Abstract
As a gram-negative intracellular bacterial pathogen, Salmonella enterica serovar Typhimurium (S. Typhimurium) invades different cell types including macrophages. Its infection in macrophages induces robust innate immune responses that are featured by proinflammatory and type I interferon (IFN) responses. The type III secretion systems (T3SSs) of S. Typhimurium play a crucial role in activating host inflammasome pathways. It has been recognized that the inflammasome pathways inhibit the type I IFN cascade. However, the potential role of T3SS in regulating the type I IFN response and the underlying mechanisms are largely unknown. In this study, we showed that S. Typhimurium infection activated strong proinflammatory, type I IFN and IFN-stimulated genes (ISGs) expression in macrophages. Furthermore, we showed that T3SS-defective S. Typhimurium mutant ΔinvC elicited attenuated inflammatory response but enhanced type I IFN and ISGs expression. Additionally, the inhibition of caspase-1 by a specific inhibitor VX-765 resulted in increased type I IFN response. Moreover, cell-permeable pan-caspase inhibitor Z-VAD-FMK also enhanced the type I IFN response upon S. Typhimurium infection. Intriguingly, compared with exponential phase S. Typhimurium infection, stationary phase bacteria triggered higher levels of type I IFN responses. Finally, the inhibition of caspase-1 by VX-765 substantially increased the intracellular S. Typhimurium burden. In conclusion, we demonstrated that the proinflammatory response induced by S. Typhimurium T3SS can inhibit the type I IFN response, which provides insight into the role of T3SS in orchestrating innate immunity during S. Typhimurium infection.
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Affiliation(s)
- Jingjing Tang
- State Key Laboratory of Crop Stress Biology for Arid Areas, Shaanxi Key Laboratory of Agricultural and Environmental Microbiology, College of Life Sciences, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Yanchao Gu
- State Key Laboratory of Crop Stress Biology for Arid Areas, Shaanxi Key Laboratory of Agricultural and Environmental Microbiology, College of Life Sciences, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Xiao Wang
- State Key Laboratory of Crop Stress Biology for Arid Areas, Shaanxi Key Laboratory of Agricultural and Environmental Microbiology, College of Life Sciences, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Yi Luo
- State Key Laboratory of Crop Stress Biology for Arid Areas, Shaanxi Key Laboratory of Agricultural and Environmental Microbiology, College of Life Sciences, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Fuhua Zhang
- State Key Laboratory of Crop Stress Biology for Arid Areas, Shaanxi Key Laboratory of Agricultural and Environmental Microbiology, College of Life Sciences, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Jingcai Zheng
- State Key Laboratory of Crop Stress Biology for Arid Areas, Shaanxi Key Laboratory of Agricultural and Environmental Microbiology, College of Life Sciences, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Yao Wang
- State Key Laboratory of Crop Stress Biology for Arid Areas, Shaanxi Key Laboratory of Agricultural and Environmental Microbiology, College of Life Sciences, Northwest A&F University, Yangling, Shaanxi 712100, China
| | - Xihui Shen
- State Key Laboratory of Crop Stress Biology for Arid Areas, Shaanxi Key Laboratory of Agricultural and Environmental Microbiology, College of Life Sciences, Northwest A&F University, Yangling, Shaanxi 712100, China.
| | - Lei Xu
- State Key Laboratory of Crop Stress Biology for Arid Areas, Shaanxi Key Laboratory of Agricultural and Environmental Microbiology, College of Life Sciences, Northwest A&F University, Yangling, Shaanxi 712100, China.
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