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Araújo FR, da Silva AL, de Oliveira L, Correa-Silva S, Bevilacqua E. Cytotoxicity and induction of proinflammatory cytokines in placental explant cells following azathioprine exposure. Placenta 2025:S0143-4004(25)00143-2. [PMID: 40413138 DOI: 10.1016/j.placenta.2025.05.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Revised: 04/14/2025] [Accepted: 05/05/2025] [Indexed: 05/27/2025]
Abstract
Immunosuppressive drugs offer hope for the survival and motherhood of women with various disorders. Although the systemic side effects of these drugs on mothers have been studied, their impact on the placenta remains poorly understood, which can negatively affect fetal and postnatal development. This study investigated the effects of Azathioprine, an immunosuppressive drug, on the chorionic villi of human placentas from healthy pregnancies, focusing on cellular vitality and pro-inflammatory cytokines expression. Chorionic villi from term placentas were cultured and treated with Azathioprine at concentrations ranging from 0 to 100 ng/mL for 24 h. Azathioprine reduced mitochondrial metabolic activity (MTT assay) at all concentrations tested (p < 0.05) and increased cellular injury rates (LDH assay) at 50 and 100 ng/mL (p < 0.05). It also elevated protein (at 12.5 and 25 ng/mL, p < 0.05) and gene expression levels of interleukin (IL)-1β (12.5 ng/mL, p < 0.05). Protein levels of IL-18 increased significantly following Azathioprine exposure (p < 0.05), along with cleaved Caspase-1 (p = 0.003) and phosphorylated NF-κB levels (p < 0.05), compared to controls. IL-18 gene expression was elevated only at 12.5 ng/mL (p < 0.0005). These findings suggest that Azathioprine creates a cytotoxic microenvironment that disrupts the metabolism of chorionic villi, leading to injury and activation of pro-inflammatory cytokine expression. Such changes may contribute to an imbalance in placental homeostasis, potentially associated with adverse maternal and neonatal outcomes that warrant further investigation.
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Affiliation(s)
- Franciele Rodrigues Araújo
- Laboratory for Studies of the Trophoblast Biology, Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, SP, Brazil
| | - Adriana Lopes da Silva
- Laboratory for Studies of the Trophoblast Biology, Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, SP, Brazil
| | - Leandro de Oliveira
- Department of Gynecology and Obstetrics, São Paulo State University (UNESP), Medical School, Botucatu, SP, Brazil
| | - Simone Correa-Silva
- Laboratory for Studies of the Trophoblast Biology, Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, SP, Brazil; Laboratory of Clinical Pediatrics (LIM36), Hospital Das Clinicas HCFMUSP, Faculty of Medicine, University of Sao Paulo, SP, Brazil
| | - Estela Bevilacqua
- Laboratory for Studies of the Trophoblast Biology, Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, SP, Brazil.
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2
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Zengeler KE, Hollis A, Deutsch TCJ, Samuels JD, Ennerfelt H, Moore KA, Steacy EJ, Sabapathy V, Sharma R, Patel MK, Lukens JR. Inflammasome signaling in astrocytes modulates hippocampal plasticity. Immunity 2025:S1074-7613(25)00170-0. [PMID: 40318630 DOI: 10.1016/j.immuni.2025.04.007] [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: 04/18/2024] [Revised: 12/13/2024] [Accepted: 04/08/2025] [Indexed: 05/07/2025]
Abstract
Emerging evidence indicates that a baseline level of controlled innate immune signaling is required to support proper brain function. However, little is known about the function of most innate immune pathways in homeostatic neurobiology. Here, we report a role for astrocyte-dependent inflammasome signaling in regulating hippocampal plasticity. Inflammasomes are multiprotein complexes that promote caspase-1-mediated interleukin (IL)-1 and IL-18 production in response to pathogens and tissue damage. We observed that inflammasome complex formation was regularly detected under homeostasis in hippocampal astrocytes and that its assembly is dynamically regulated in response to learning and regional activity. Conditional ablation of caspase-1 in astrocytes limited hyperexcitability in an acute seizure model and impacted hippocampal plasticity via modulation of synaptic protein density, neuronal activity, and perineuronal net coverage. Caspase-1 and IL-18 regulated hippocampal IL-33 production and related plasticity. These findings reveal a homeostatic function for astrocyte inflammasome activity in regulating hippocampal physiology in health and disease.
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Affiliation(s)
- Kristine E Zengeler
- Center for Brain Immunology and Glia (BIG), Department of Neuroscience, University of Virginia, Charlottesville, VA 22908, USA.
| | - Ava Hollis
- Center for Brain Immunology and Glia (BIG), Department of Neuroscience, University of Virginia, Charlottesville, VA 22908, USA
| | - Tyler C J Deutsch
- Department of Anesthesiology, University of Virginia, Charlottesville, VA 22908, USA
| | - Joshua D Samuels
- Center for Brain Immunology and Glia (BIG), Department of Neuroscience, University of Virginia, Charlottesville, VA 22908, USA; Neuroscience Graduate Program, University of Virginia, Charlottesville, VA 22908, USA; Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, USA
| | - Hannah Ennerfelt
- Department of Neurology and Neurological Sciences, Stanford University, Palo Alto, CA 24304, USA
| | - Katelyn A Moore
- Center for Brain Immunology and Glia (BIG), Department of Neuroscience, University of Virginia, Charlottesville, VA 22908, USA
| | - Eric J Steacy
- Center for Brain Immunology and Glia (BIG), Department of Neuroscience, University of Virginia, Charlottesville, VA 22908, USA
| | - Vikram Sabapathy
- Division of Nephrology, Department of Medicine, Center for Immunity, Inflammation and Regenerative Medicine (CIIR), University of Virginia, Charlottesville, VA 22908, USA
| | - Rahul Sharma
- Division of Nephrology, Department of Medicine, Center for Immunity, Inflammation and Regenerative Medicine (CIIR), University of Virginia, Charlottesville, VA 22908, USA
| | - Manoj K Patel
- Department of Anesthesiology, University of Virginia, Charlottesville, VA 22908, USA; Neuroscience Graduate Program, University of Virginia, Charlottesville, VA 22908, USA
| | - John R Lukens
- Center for Brain Immunology and Glia (BIG), Department of Neuroscience, University of Virginia, Charlottesville, VA 22908, USA; Neuroscience Graduate Program, University of Virginia, Charlottesville, VA 22908, USA.
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Kim DH, Choi G, Song EB, Lee H, Kim J, Jang YS, Park J, Chi S, Han J, Kim SM, Kim D, Bae SH, Lee HW, Park JY, Kang SG, Cha SH, Han YH. Treatment of IL-18-binding protein biologics suppresses fibrotic progression in metabolic dysfunction-associated steatohepatitis. Cell Rep Med 2025; 6:102047. [PMID: 40239621 PMCID: PMC12047490 DOI: 10.1016/j.xcrm.2025.102047] [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: 10/07/2023] [Revised: 10/18/2024] [Accepted: 03/07/2025] [Indexed: 04/18/2025]
Abstract
Metabolic dysfunction-associated steatohepatitis (MASH) is a chronic liver disease characterized by inflammation and fibrosis, with enhanced interleukin-18 (IL-18) signaling. IL-18-binding protein (IL-18BP) neutralizes IL-18, but its therapeutic potential in MASH is unclear. We find elevated IL-18BP and IL-18 levels in patients with MASH and mice, with free IL-18 correlating with disease severity. IL-18 stimulates interferon-gamma (IFNγ) production in CD4 T cells, increasing hepatic IL-18BP. IL-18BP-deficient mice show worsened liver inflammation and fibrosis. We develop a human IL-18BP biologics (APB-R3) and inject it to mice to evaluate its pharmacologic efficacy. APB-R3 significantly improves MASH in reducing fibrosis and inflammation and inhibits hepatic stellate cell activation via the cGMP pathway. This study proposes that abrogation of IL-18 signaling by boosting IL-18BP can strongly inhibit the development of MASH-induced fibrosis, and our engineered IL-18BP biologics can become a promising therapeutic candidate for curing MASH.
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Affiliation(s)
- Dong-Hyun Kim
- Laboratory of Pathology and Physiology, College of Pharmacy, Kangwon National University, Chuncheon 24341, South Korea
| | - Gona Choi
- Laboratory of Pathology and Physiology, College of Pharmacy, Kangwon National University, Chuncheon 24341, South Korea
| | - Eun-Bi Song
- Laboratory of Pathology and Physiology, College of Pharmacy, Kangwon National University, Chuncheon 24341, South Korea
| | - Hanna Lee
- Laboratory of Pathology and Physiology, College of Pharmacy, Kangwon National University, Chuncheon 24341, South Korea; Multidimensional Genomics Research Center, Kangwon National University, Chuncheon 24341, South Korea
| | - Jaehui Kim
- Division of Biomedical Convergence, College of Biomedical Science, Kangwon National University, Chuncheon 24341, South Korea; Institute of Bioscience and Biotechnology, College of Biomedical Science, Kangwon National University, Chuncheon 24341, South Korea
| | - Young-Saeng Jang
- Division of Biomedical Convergence, College of Biomedical Science, Kangwon National University, Chuncheon 24341, South Korea; Institute of Bioscience and Biotechnology, College of Biomedical Science, Kangwon National University, Chuncheon 24341, South Korea
| | - JinJoo Park
- AprilBio Co., Ltd, Biomedical Science Building, Kangwon National University, Chuncheon 24341, South Korea
| | - Susan Chi
- AprilBio Co., Ltd, Biomedical Science Building, Kangwon National University, Chuncheon 24341, South Korea
| | - Jaekyu Han
- AprilBio Co., Ltd, Biomedical Science Building, Kangwon National University, Chuncheon 24341, South Korea
| | - Sun-Mi Kim
- AprilBio Co., Ltd, Biomedical Science Building, Kangwon National University, Chuncheon 24341, South Korea
| | - Dongyoon Kim
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Soo Han Bae
- Severance Biomedical Science Institute, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, South Korea
| | - Hye Won Lee
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, South Korea
| | - Jun Yong Park
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, South Korea
| | - Seung Goo Kang
- Division of Biomedical Convergence, College of Biomedical Science, Kangwon National University, Chuncheon 24341, South Korea; Institute of Bioscience and Biotechnology, College of Biomedical Science, Kangwon National University, Chuncheon 24341, South Korea.
| | - Sang-Hoon Cha
- Institute of Bioscience and Biotechnology, College of Biomedical Science, Kangwon National University, Chuncheon 24341, South Korea; AprilBio Co., Ltd, Biomedical Science Building, Kangwon National University, Chuncheon 24341, South Korea.
| | - Yong-Hyun Han
- Laboratory of Pathology and Physiology, College of Pharmacy, Kangwon National University, Chuncheon 24341, South Korea; Multidimensional Genomics Research Center, Kangwon National University, Chuncheon 24341, South Korea.
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Kawano Y, Kawano H, LaMere MW, LaMere EA, Byun DK, McGrath KE, Palis J, Bajaj J, Liesveld JL, Katayama Y, Yamazaki S, Kapur R, Calvi LM, Ho TC, Becker MW. IL-1R1 and IL-18 signals regulate mesenchymal stromal cells in an aged murine model of myelodysplastic syndromes. Blood 2025; 145:1632-1644. [PMID: 39841001 PMCID: PMC12000655 DOI: 10.1182/blood.2024024818] [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: 04/10/2024] [Revised: 12/12/2024] [Accepted: 12/16/2024] [Indexed: 01/23/2025] Open
Abstract
ABSTRACT Myelodysplastic syndromes (MDS) are age-related diseases characterized by bone marrow (BM) dysfunction and an increased risk for developing acute leukemia. Although there is growing evidence that highlight the crucial role of the BM microenvironment (BMME) in MDS, the specific influence of inflammation on BMME changes and the potential benefits of targeting cytokines therapeutically remain to be elucidated. We previously found that interleukin-1 (IL-1) is a driver of aging phenotypes of the BMME and hematopoietic stem and progenitor cells (HSPCs). In this study, BM samples from patients with MDS demonstrated upregulated levels of IL-1 family cytokines, including IL-18. Using highly purified primary BM-derived mesenchymal stromal cells (MSCs), both IL-1b and IL-18 were found to exert direct effects on MSCs, thus influencing their ability to support HSPCs and erythroid progenitors. This confirms the significant involvement of both these IL-1 family cytokines in regulating the BM niche. Furthermore, targeting IL-1 receptor type 1 mitigated these aging phenotypes in older mice. We subsequently employed an age-appropriate murine model of MDS by transplanting NUP98-HOXD13 transgenic mice (NHD13Tg) cells into aged wild-type mice. Treatment with inhibitors that targeted IL-1 receptor-associated kinase 4 (IRAK4) and NOD-like receptor family pyrin domain containing 3 (NLRP3) reversed the proliferation of dysfunctional MSCs and enhanced their functionality. In addition, IRAK4 inhibition selectively suppressed MDS clonal cells while sparing non-MDS cells in the BM. These findings suggest that targeting IL-1 signaling holds promise for MDS treatment by addressing the underlying myeloid malignancy and restoring the altered BMME via BM-MSCs.
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Affiliation(s)
- Yuko Kawano
- James P. Wilmot Cancer Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY
- Division of Endocrinology and Metabolism, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY
- Division of Cell Regulation, Center of Experimental Medicine and System Biology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Hiroki Kawano
- James P. Wilmot Cancer Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY
- Division of Hematology/Oncology, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY
| | - Mark W. LaMere
- James P. Wilmot Cancer Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY
- Division of Hematology/Oncology, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY
| | - Elizabeth A. LaMere
- James P. Wilmot Cancer Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY
- Division of Endocrinology and Metabolism, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY
- Division of Hematology/Oncology, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY
| | - Daniel K. Byun
- James P. Wilmot Cancer Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY
- Division of Endocrinology and Metabolism, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY
- Division of Hematology/Oncology, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY
| | - Kathleen E. McGrath
- Department of Pediatrics, University of Rochester Medical Center, Rochester, NY
| | - James Palis
- Department of Pediatrics, University of Rochester Medical Center, Rochester, NY
| | - Jeevisha Bajaj
- James P. Wilmot Cancer Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY
- Department of Biomedical Genetics, University of Rochester, Rochester, NY
| | - Jane L. Liesveld
- James P. Wilmot Cancer Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY
- Division of Hematology/Oncology, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY
| | - Yoshio Katayama
- Division of Hematology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Satoshi Yamazaki
- Division of Cell Regulation, Center of Experimental Medicine and System Biology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Reuben Kapur
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN
| | - Laura M. Calvi
- James P. Wilmot Cancer Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY
- Division of Endocrinology and Metabolism, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY
| | - Tzu-Chieh Ho
- James P. Wilmot Cancer Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY
- Division of Hematology/Oncology, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN
| | - Michael W. Becker
- James P. Wilmot Cancer Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY
- Division of Hematology/Oncology, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY
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Gui R, Ren Y, Wang Z, Li Y, Wu C, Li X, Li M, Li Y, Qian L, Xiong Y. Deciphering interleukin-18 in diabetes and its complications: Biological features, mechanisms, and therapeutic perspectives. Obes Rev 2024; 25:e13818. [PMID: 39191434 DOI: 10.1111/obr.13818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 07/16/2024] [Accepted: 08/02/2024] [Indexed: 08/29/2024]
Abstract
Interleukin-18 (IL-18), a potent and multifunctional pro-inflammatory cytokine, plays a critical role in regulating β-cell failure, β-cell death, insulin resistance, and various complications of diabetes mellitus (DM). It exerts its effects by triggering various signaling pathways, enhancing the production of pro-inflammatory cytokines and nitric oxide (NO), as well as promoting immune cells infiltration and β-cells death. Abnormal alterations in IL-18 levels have been revealed to be strongly associated with the onset and development of DM and its complications. Targeting IL-18 may present a novel and promising approach for DM therapy. An increasing number of IL-18 inhibitors, including chemical and natural inhibitors, have been developed and have been shown to protect against DM and diabetic complications. This review provides a comprehensive understanding of the production, biological functions, action mode, and activated signaling pathways of IL-18. Next, we shed light on how IL-18 contributes to the pathogenesis of DM and its associated complications with links to its roles in the modulation of β-cell failure and death, insulin resistance in various tissues, and pancreatitis. Furthermore, the therapeutic potential of targeting IL-18 for the diagnosis and treatment of DM is also highlighted. We hope that this review will help us better understand the functions of IL-18 in the pathogenesis of DM and its complications, providing novel strategies for DM diagnosis and treatment.
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Affiliation(s)
- Runlin Gui
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, Shaanxi, China
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No.3 Hospital, the Affiliated Hospital of Northwest University, Xi'an, Shaanxi, China
| | - Yuanyuan Ren
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, Shaanxi, China
| | - Zhen Wang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, Shaanxi, China
| | - Yang Li
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, Shaanxi, China
| | - Chengsong Wu
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, Shaanxi, China
| | - Xiaofang Li
- Department of Gastroenterology, Xi'an No.3 Hospital, the Affiliated Hospital of Northwest University, Xi'an, Shaanxi, China
| | - Man Li
- Department of Endocrinology, Xi'an No.3 Hospital, the Affiliated Hospital of Northwest University, Xi'an, Shaanxi, China
| | - Yujia Li
- Department of Traditional Chinese Medicine, Xi'an No.3 Hospital, the Affiliated Hospital of Northwest University, Xi'an, Shaanxi, China
| | - Lu Qian
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, Shaanxi, China
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No.3 Hospital, the Affiliated Hospital of Northwest University, Xi'an, Shaanxi, China
- Scientific Research Center, Xi'an Mental Health Center, Xi'an, Shaanxi, China
| | - Yuyan Xiong
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, Shaanxi, China
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No.3 Hospital, the Affiliated Hospital of Northwest University, Xi'an, Shaanxi, China
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Kyriakopoulos AM, Nigh G, McCullough PA, Seneff S. Clinical rationale for dietary lutein supplementation in long COVID and mRNA vaccine injury syndromes. F1000Res 2024; 13:191. [PMID: 39526116 PMCID: PMC11549548 DOI: 10.12688/f1000research.143517.3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/14/2024] [Indexed: 11/16/2024] Open
Abstract
Lutein, a plant-derived xanthophyl-carotenoid, is an exceptional antioxidant and anti-inflammatory constituent found in food. High dietary intake of lutein is beneficial against eye disease, improves cardiometabolic health, protects from neurodegenerative diseases, and is beneficial for liver, kidney, and respiratory health. Lutein protects against oxidative and nitrosative stress, both of which play a major role in long COVID and mRNA vaccination injury syndromes. Lutein is an important natural agent for therapeutic use against oxidative and nitrosative stress in chronic illnesses such as cardiovascular and neurodegenerative diseases and cancer. It can also potentially inhibit spike protein-induced inflammation. Rich dietary supplementation of lutein, naturally derived in non-biodegradable Extra Virgin Olive Oil (EVOO), can most optimally be used against oxidative and nitrosative stress during post-COVID and mRNA vaccination injury syndromes. Due to its high oleic acid (OA) content, EVOO supports optimal absorption of dietary lutein. The main molecular pathways by which the SARS-CoV-2 spike protein induces pathology, nuclear factor kappa-light-chain-enhancer activated B cells (NF-κB) and activated protein (AP)-1, can be suppressed by lutein. Synergy with other natural compounds for spike protein detoxification is likely.
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Affiliation(s)
| | - Greg Nigh
- Naturopathic Oncologist, Immersion Health, Portland, Oregon, USA
| | | | - Stephanie Seneff
- Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
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Hédou J, Marić I, Bellan G, Einhaus J, Gaudillière DK, Ladant FX, Verdonk F, Stelzer IA, Feyaerts D, Tsai AS, Ganio EA, Sabayev M, Gillard J, Amar J, Cambriel A, Oskotsky TT, Roldan A, Golob JL, Sirota M, Bonham TA, Sato M, Diop M, Durand X, Angst MS, Stevenson DK, Aghaeepour N, Montanari A, Gaudillière B. Discovery of sparse, reliable omic biomarkers with Stabl. Nat Biotechnol 2024; 42:1581-1593. [PMID: 38168992 PMCID: PMC11217152 DOI: 10.1038/s41587-023-02033-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Accepted: 10/16/2023] [Indexed: 01/05/2024]
Abstract
Adoption of high-content omic technologies in clinical studies, coupled with computational methods, has yielded an abundance of candidate biomarkers. However, translating such findings into bona fide clinical biomarkers remains challenging. To facilitate this process, we introduce Stabl, a general machine learning method that identifies a sparse, reliable set of biomarkers by integrating noise injection and a data-driven signal-to-noise threshold into multivariable predictive modeling. Evaluation of Stabl on synthetic datasets and five independent clinical studies demonstrates improved biomarker sparsity and reliability compared to commonly used sparsity-promoting regularization methods while maintaining predictive performance; it distills datasets containing 1,400-35,000 features down to 4-34 candidate biomarkers. Stabl extends to multi-omic integration tasks, enabling biological interpretation of complex predictive models, as it hones in on a shortlist of proteomic, metabolomic and cytometric events predicting labor onset, microbial biomarkers of pre-term birth and a pre-operative immune signature of post-surgical infections. Stabl is available at https://github.com/gregbellan/Stabl .
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Affiliation(s)
- Julien Hédou
- Department of Anesthesiology, Perioperative & Pain Medicine, Stanford University, Stanford, CA, USA
| | - Ivana Marić
- Department of Pediatrics, Stanford University, Stanford, CA, USA
| | - Grégoire Bellan
- Télécom Paris, Institut Polytechnique de Paris, Paris, France
| | - Jakob Einhaus
- Department of Anesthesiology, Perioperative & Pain Medicine, Stanford University, Stanford, CA, USA
- Department of Pathology and Neuropathology, University Hospital and Comprehensive Cancer Center Tübingen, Tübingen, Germany
| | - Dyani K Gaudillière
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University, Stanford, CA, USA
| | | | - Franck Verdonk
- Department of Anesthesiology, Perioperative & Pain Medicine, Stanford University, Stanford, CA, USA
- Sorbonne University, GRC 29, AP-HP, DMU DREAM, Department of Anesthesiology and Intensive Care, Hôpital Saint-Antoine, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Ina A Stelzer
- Department of Anesthesiology, Perioperative & Pain Medicine, Stanford University, Stanford, CA, USA
- Department of Pathology, University of California San Diego, La Jolla, CA, USA
| | - Dorien Feyaerts
- Department of Anesthesiology, Perioperative & Pain Medicine, Stanford University, Stanford, CA, USA
| | - Amy S Tsai
- Department of Anesthesiology, Perioperative & Pain Medicine, Stanford University, Stanford, CA, USA
| | - Edward A Ganio
- Department of Anesthesiology, Perioperative & Pain Medicine, Stanford University, Stanford, CA, USA
| | - Maximilian Sabayev
- Department of Anesthesiology, Perioperative & Pain Medicine, Stanford University, Stanford, CA, USA
| | - Joshua Gillard
- Department of Anesthesiology, Perioperative & Pain Medicine, Stanford University, Stanford, CA, USA
- Department of Medical BioSciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Jonas Amar
- Department of Anesthesiology, Perioperative & Pain Medicine, Stanford University, Stanford, CA, USA
| | - Amelie Cambriel
- Department of Anesthesiology, Perioperative & Pain Medicine, Stanford University, Stanford, CA, USA
| | - Tomiko T Oskotsky
- Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA, USA
| | - Alennie Roldan
- Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA, USA
| | - Jonathan L Golob
- Department of Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Marina Sirota
- Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA, USA
| | - Thomas A Bonham
- Department of Anesthesiology, Perioperative & Pain Medicine, Stanford University, Stanford, CA, USA
| | - Masaki Sato
- Department of Anesthesiology, Perioperative & Pain Medicine, Stanford University, Stanford, CA, USA
| | - Maïgane Diop
- Department of Anesthesiology, Perioperative & Pain Medicine, Stanford University, Stanford, CA, USA
| | - Xavier Durand
- École Polytechnique, Institut Polytechnique de Paris, Paris, France
| | - Martin S Angst
- Department of Anesthesiology, Perioperative & Pain Medicine, Stanford University, Stanford, CA, USA
| | | | - Nima Aghaeepour
- Department of Anesthesiology, Perioperative & Pain Medicine, Stanford University, Stanford, CA, USA
- Department of Pediatrics, Stanford University, Stanford, CA, USA
- Department of Biomedical Data Science, Stanford University, Stanford, CA, USA
| | - Andrea Montanari
- Department of Statistics, Stanford University, Stanford, CA, USA
- Department of Electrical Engineering, Stanford University, Stanford, CA, USA
| | - Brice Gaudillière
- Department of Anesthesiology, Perioperative & Pain Medicine, Stanford University, Stanford, CA, USA.
- Department of Pediatrics, Stanford University, Stanford, CA, USA.
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8
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Park J, Kim YJ, Lee M, Kim D, Sim J, Cho K, Moon JH, Sung KS, Lee DH, Lim J. Correlation of LLT-1 and NLRC4 inflammasome and its effect on glioblastoma prognosis. J Neurooncol 2024; 169:543-553. [PMID: 38907949 DOI: 10.1007/s11060-024-04750-y] [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: 05/21/2024] [Accepted: 06/13/2024] [Indexed: 06/24/2024]
Abstract
PURPOSE LLT-1 is a well-known ligand for the natural killer (NK) cell inhibitory receptor NKRP1A. Here, we examined NLRC4 inflammasome components and LLT-1 expression in glioblastoma (GBM) tissues to elucidate potential associations and interactions between these factors. METHODS GBM tissues were collected for RNA sequencing (RNA-seq) and Immunofluorescent experiments. Colocalization of LLT-1 and other proteins was assessed by immunofluorescence. Computational analyses utilized RNA-seq data from 296 to 52 patients from the Chinese Glioma Genome Atlas and CHA medical records, respectively. These data were subjected to survival, non-negative matrix factorization clustering, Gene Ontology enrichment, and protein-protein interaction analyses. Receptor-ligand interactions between tumor and immune cells were confirmed by single-cell RNA-seq analysis. RESULTS In GBM tissues, LLT-1 was predominantly colocalized with glial fibrillary acidic protein (GFAP)-expressing astrocytes, but not with microglial markers like Iba-1. Additionally, LLT-1 and activated NLRC4 inflammasomes were mainly co-expressed in intratumoral astrocytes, suggesting an association between LLT-1, NLRC4, and glioma malignancy. High LLT-1 expression correlates with poor prognosis, particularly in the mesenchymal subtype, and is associated with TNF and NOD-like receptor signaling pathway enrichment, indicating a potential role in tumor inflammation and progression. At the single-cell level, mesenchymal-like malignant cells showed high NF, NLR, and IL-1 signaling pathway enrichment compared to other malignant cell types. CONCLUSION We revealed an association between NLRC4 inflammasome activity and LLT-1 expression, suggesting a novel regulatory pathway involving TNF, inflammasomes, and IL-1, potentially offering new NK-cell-mediated anti-glioma approaches.
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Affiliation(s)
- JeongMan Park
- Department of Biomedical Science, College of Life Science, CHA University, Seongnam, Korea
- Department of Medicine, College of Medicine, Hallym University, Chuncheon, Korea
- CHA Institute for Future Medicine, Medical Center Research Institute, Seongnam, Korea
| | - Yu Jin Kim
- Department of Biomedical Science, College of Life Science, CHA University, Seongnam, Korea
- CHA Institute for Future Medicine, Medical Center Research Institute, Seongnam, Korea
| | - Minwook Lee
- Department of Biomedical Science, College of Life Science, CHA University, Seongnam, Korea
| | - Dongkil Kim
- Department of Biomedical Science, College of Life Science, CHA University, Seongnam, Korea
- CHA Institute for Future Medicine, Medical Center Research Institute, Seongnam, Korea
| | - JeongMin Sim
- Department of Biomedical Science, College of Life Science, CHA University, Seongnam, Korea
- CHA Institute for Future Medicine, Medical Center Research Institute, Seongnam, Korea
| | - Kyunggi Cho
- Department of Neurosurgery, Bundang CHA Medical Center, CHA University College of Medicine, Seongnam, Korea
| | - Ju Hyung Moon
- Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Kyoung Su Sung
- Department of Neurosurgery, Dong-A University Hospital, Dong-A University College of Medicine, Busan, Korea
| | - Dong Hyeon Lee
- CHA Institute for Future Medicine, Medical Center Research Institute, Seongnam, Korea.
- Department of Physiology, CHA University School of Medicine, Pocheon, Korea.
| | - Jaejoon Lim
- Department of Biomedical Science, College of Life Science, CHA University, Seongnam, Korea.
- CHA Institute for Future Medicine, Medical Center Research Institute, Seongnam, Korea.
- Department of Neurosurgery, Bundang CHA Medical Center, CHA University College of Medicine, Seongnam, Korea.
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9
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Herring M, Persson A, Potter R, Karlsson R, Särndahl E, Ejdebäck M. Exposing kinetic disparities between inflammasome readouts using time-resolved analysis. Heliyon 2024; 10:e32023. [PMID: 38867997 PMCID: PMC11168392 DOI: 10.1016/j.heliyon.2024.e32023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Revised: 05/23/2024] [Accepted: 05/27/2024] [Indexed: 06/14/2024] Open
Abstract
The NLRP3 inflammasome is an intracellular multiprotein complex described to be involved in both an effective host response to infectious agents and various diseases. Investigation into the NLRP3 inflammasome has been extensive in the past two decades, and often revolves around the analysis of a few specific readouts, including ASC-speck formation, caspase-1 cleavage or activation, and cleavage and release of IL-1β and/or IL-18. Quantification of these readouts is commonly undertaken as an endpoint analysis, where the presence of each positive outcome is assessed independently of the others. In this study, we apply time-resolved analysis of a human macrophage model (differentiated THP-1-ASC-GFP cells) to commonly accessible methods. This approach yields the additional quantifiable metrics time-resolved absolute change and acceleration, allowing comparisons between readouts. Using this methodological approach, we reveal (potential) discrepancies between inflammasome-related readouts that otherwise might go undiscovered. The study highlights the importance of time-resolved data in general and may be further extended as well as incorporated into other areas of research.
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Affiliation(s)
- Matthew Herring
- School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
- Inflammatory Response and Infection Susceptibility Centre (iRiSC), Örebro University, Örebro, Sweden
- School of Bioscience, Systems Biology Research Centre, University of Skövde, Skövde, Sweden
| | - Alexander Persson
- School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
- Inflammatory Response and Infection Susceptibility Centre (iRiSC), Örebro University, Örebro, Sweden
| | - Ryan Potter
- School of Bioscience, Systems Biology Research Centre, University of Skövde, Skövde, Sweden
- Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Göteborg University, Göteborg, Sweden
| | - Roger Karlsson
- Nanoxis Consulting AB, Göteborg, Sweden
- Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, Göteborg University, Göteborg, Sweden
- Department of Clinical Microbiology, Sahlgrenska University Hospital, Region Västra Götaland, Göteborg, Sweden
| | - Eva Särndahl
- School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
- Inflammatory Response and Infection Susceptibility Centre (iRiSC), Örebro University, Örebro, Sweden
| | - Mikael Ejdebäck
- School of Bioscience, Systems Biology Research Centre, University of Skövde, Skövde, Sweden
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10
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Saadatagah S, Naderian M, Uddin M, Dikilitas O, Niroula A, Schuermans A, Selvin E, Hoogeveen RC, Matsushita K, Nambi V, Yu B, Chen LY, Bick AG, Ebert BL, Honigberg MC, Li N, Shah A, Natarajan P, Kullo IJ, Ballantyne CM. Atrial Fibrillation and Clonal Hematopoiesis in TET2 and ASXL1. JAMA Cardiol 2024; 9:497-506. [PMID: 38598228 PMCID: PMC11007653 DOI: 10.1001/jamacardio.2024.0459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Accepted: 02/19/2024] [Indexed: 04/11/2024]
Abstract
Importance Clonal hematopoiesis of indeterminate potential (CHIP) may contribute to the risk of atrial fibrillation (AF) through its association with inflammation and cardiac remodeling. Objective To determine whether CHIP was associated with AF, inflammatory and cardiac biomarkers, and cardiac structural changes. Design, Setting, and Participants This was a population-based, prospective cohort study in participants of the Atherosclerosis Risk in Communities (ARIC) study and UK Biobank (UKB) cohort. Samples were collected and echocardiography was performed from 2011 to 2013 in the ARIC cohort, and samples were collected from 2006 to 2010 in the UKB cohort. Included in this study were adults without hematologic malignancies, mitral valve stenosis, or previous mitral valve procedure from both the ARIC and UKB cohorts; additionally, participants without hypertrophic cardiomyopathy and congenital heart disease from the UKB cohort were also included. Data analysis was completed in 2023. Exposures CHIP (variant allele frequency [VAF] ≥2%), common gene-specific CHIP subtypes (DNMT3A, TET2, ASXL1), large CHIP (VAF ≥10%), inflammatory and cardiac biomarkers (high-sensitivity C-reactive protein, interleukin 6 [IL-6], IL-18, high-sensitivity troponin T [hs-TnT] and hs-TnI, N-terminal pro-B-type natriuretic peptide), and echocardiographic indices. Main Outcome Measure Incident AF. Results A total of 199 982 adults were included in this study. In ARIC participants (4131 [2.1%]; mean [SD] age, 76 [5] years; 2449 female [59%]; 1682 male [41%]; 935 Black [23%] and 3196 White [77%]), 1019 had any CHIP (24.7%), and 478 had large CHIP (11.6%). In UKB participants (195 851 [97.9%]; mean [SD] age, 56 [8] years; 108 370 female [55%]; 87 481 male [45%]; 3154 Black [2%], 183 747 White [94%], and 7971 other race [4%]), 11 328 had any CHIP (5.8%), and 5189 had large CHIP (2.6%). ARIC participants were followed up for a median (IQR) period of 7.0 (5.3-7.7) years, and UKB participants were followed up for a median (IQR) period of 12.2 (11.3-13.0) years. Meta-analyzed hazard ratios for AF were 1.12 (95% CI, 1.01-1.25; P = .04) for participants with vs without large CHIP, 1.29 (95% CI, 1.05-1.59; P = .02) for those with vs without large TET2 CHIP (seen in 1340 of 197 209 [0.67%]), and 1.45 (95% CI, 1.02-2.07; P = .04) for those with vs without large ASXL1 CHIP (seen in 314 of 197 209 [0.16%]). Large TET2 CHIP was associated with higher IL-6 levels. Additionally, large ASXL1 was associated with higher hs-TnT level and increased left ventricular mass index. Conclusions and Relevance Large TET2 and ASXL1, but not DNMT3A, CHIP was associated with higher IL-6 level, indices of cardiac remodeling, and increased risk for AF. Future research is needed to elaborate on the mechanisms driving the associations and to investigate potential interventions to reduce the risk.
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Affiliation(s)
- Seyedmohammad Saadatagah
- Department of Medicine, Baylor College of Medicine, Houston, Texas
- Center for Translational Research on Inflammatory Diseases, Baylor College of Medicine, Houston, Texas
| | | | - Mesbah Uddin
- Cardiovascular Research Center, Massachusetts General Hospital, Boston
| | - Ozan Dikilitas
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota
- Program in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, Massachusetts
| | - Abhishek Niroula
- Program in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, Massachusetts
- Department of Laboratory Medicine, Lund University, Lund, Sweden
- Institute of Biomedicine, SciLifeLab, University of Gothenburg, Gothenburg, Sweden
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Art Schuermans
- Cardiovascular Research Center, Massachusetts General Hospital, Boston
- Program in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, Massachusetts
- Faculty of Medicine, KU Leuven, Leuven, Belgium
| | - Elizabeth Selvin
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Ron C. Hoogeveen
- Department of Medicine, Baylor College of Medicine, Houston, Texas
| | - Kunihiro Matsushita
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Vijay Nambi
- Department of Medicine, Baylor College of Medicine, Houston, Texas
- Department of Medicine, Michael E. DeBakey VA Medical Center, Veterans Affairs Hospital, Houston, Texas
| | - Bing Yu
- Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston
| | - Lin Yee Chen
- Department of Medicine, University of Minnesota, Minneapolis
| | | | - Benjamin L. Ebert
- Program in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, Massachusetts
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
- Center for Prevention of Progression, Dana-Farber Cancer Institute, Boston, Massachusetts
- Howard Hughes Medical Institute, Boston, Massachusetts
- Department of Medicine, Harvard Medical School, Boston, Massachusetts
| | - Michael C. Honigberg
- Cardiovascular Research Center, Massachusetts General Hospital, Boston
- Program in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, Massachusetts
- Department of Medicine, Harvard Medical School, Boston, Massachusetts
| | - Na Li
- Department of Medicine, Baylor College of Medicine, Houston, Texas
| | - Amil Shah
- Department of Medicine, University of Texas Southwestern, Dallas
| | - Pradeep Natarajan
- Cardiovascular Research Center, Massachusetts General Hospital, Boston
- Program in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, Massachusetts
- Department of Medicine, Harvard Medical School, Boston, Massachusetts
| | - Iftikhar J. Kullo
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota
- Gonda Vascular Center, Mayo Clinic, Rochester, Minnesota
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11
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Sha X, Ye H, Wang X, Xu Z, Sun A, Xiao W, Zhang T, Yang S, Yang H. GSDMD mediated pyroptosis induced inflammation of Graves' orbitopathy via the NF-κB/ AIM2/ Caspase-1 pathway. Exp Eye Res 2024; 240:109812. [PMID: 38342335 DOI: 10.1016/j.exer.2024.109812] [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: 09/14/2023] [Revised: 12/28/2023] [Accepted: 01/28/2024] [Indexed: 02/13/2024]
Abstract
Gasdermin D (GSDMD) is a key executor which triggers pyroptosis as well as an attractive checkpoint in various inflammatory and autoimmune diseases but it has yet to prove its function in Graves'orbitopathy (GO). Our aim was to investigate GSDMD levels in orbital connective tissue and serum of GO patients and then assess the association between serum levels and patients' clinical activity score (CAS). Further, GSDMD-mediated pyroptosis and the underlying mechanism in inflammatory pathogenesis in the cultured orbital fibroblasts (OFs) of GO patients were examined. OFs were collected after tumor necrosis factor (TNF)-α or interferon (IFN)-γ treatment or combination treatment at different times, and the expression of GSDMD and related molecular mechanisms were analyzed. Then, we constructed the GSDMD knockout system with siRNA and the system was further exposed to the medium with or without IFN-γ and TNF-α for a specified time. Finally, we evaluated the production of interleukin (IL)-1β and IL-18. We found that serum GSDMD levels were elevated and positively correlated with the CAS in GO patients. Meanwhile, the expression of GSDMD and N-terminal domain (NT-GSDMD) in orbital connective tissue of GO patients was augmented. Also, increased expression of GSDMD and related pyroptosis factors was observed in vitro model of GO. We further demonstrated that GSDMD-mediated pyroptosis induced inflammation via the nuclear factor kB (NF-κB)/absent in melanoma-2 (AIM-2)/caspase-1 pathway. In addition, blocking GSDMD suppressed proinflammatory cytokine production in GO. We concluded that GSDMD may be a biomarker as well as a potential target for the evaluation and treatment of inflammation related with GO.
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Affiliation(s)
- Xiaotong Sha
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Huijing Ye
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China.
| | - Xing Wang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Zhihui Xu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Anqi Sun
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Wei Xiao
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Te Zhang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Shenglan Yang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
| | - Huasheng Yang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China.
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12
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Taheri M, Tehrani HA, Daliri F, Alibolandi M, Soleimani M, Shoari A, Arefian E, Ramezani M. Bioengineering strategies to enhance the interleukin-18 bioactivity in the modern toolbox of cancer immunotherapy. Cytokine Growth Factor Rev 2024; 75:65-80. [PMID: 37813764 DOI: 10.1016/j.cytogfr.2023.09.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Revised: 09/26/2023] [Accepted: 09/26/2023] [Indexed: 10/11/2023]
Abstract
Cytokines are the first modern immunotherapeutic agents used for activation immunotherapy. Interleukin-18 (IL-18) has emerged as a potent anticancer immunostimulatory cytokine over the past three decades. IL-18, structurally is a stable protein with very low toxicity at biological doses. IL-18 promotes the process of antigen presentation and also enhances innate and acquired immune responses. It can induce the production of proinflammatory cytokines and increase tumor infiltration of effector immune cells to revert the immunosuppressive milieu of tumors. Furthermore, IL-18 can reduce tumorigenesis, suppress tumor angiogenesis, and induce tumor cell apoptosis. These characteristics present IL-18 as a promising option for cancer immunotherapy. Although several preclinical studies have reported the immunotherapeutic potential of IL-18, clinical trials using it as a monotherapy agent have reported disappointing results. These results may be due to some biological characteristics of IL-18. Several bioengineering approaches have been successfully used to correct its defects as a bioadjuvant. Currently, the challenge with this anticancer immunotherapeutic agent is mainly how to use its capabilities in a rational combinatorial therapy for clinical applications. The present study discussed the strengths and weaknesses of IL-18 as an immunotherapeutic agent, followed by comprehensive review of various promising bioengineering approaches that have been used to overcome its disadvantages. Finally, this study highlights the promising application of IL-18 in modern combinatorial therapies, such as chemotherapy, immune checkpoint blockade therapy, cell-based immunotherapy and cancer vaccines to guide future studies, circumventing the barriers to administration of IL-18 for clinical applications, and bring it to fruition as a potent immunotherapy agent in cancer treatment.
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Affiliation(s)
- Mojtaba Taheri
- Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Hossein Abdul Tehrani
- Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
| | | | - Mona Alibolandi
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Pharmaceutical Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Masoud Soleimani
- Department of Hematology and Cell Therapy, Faculty of Medical Sciences, Tarbiat Modares University, Iran
| | - Alireza Shoari
- Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA
| | - Ehsan Arefian
- Department of Microbiology, School of Biology, College of Science, University of Tehran, Tehran, Iran; Pediatric Cell and Gene Therapy Research Center, Gene, Cell & Tissue Research Institute, Tehran University of Medical Sciences, Tehran, Iran.
| | - Mohammad Ramezani
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Pharmaceutical Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
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13
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de Souza RL, Opretzka LCF, de Morais MC, Melo CDO, de Oliveira BEG, de Sousa DP, Villarreal CF, Oliveira EE. Nanoemulsion Improves the Anti-Inflammatory Effect of Intraperitoneal and Oral Administration of Carvacryl Acetate. Pharmaceuticals (Basel) 2023; 17:17. [PMID: 38276002 PMCID: PMC10821396 DOI: 10.3390/ph17010017] [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: 11/21/2023] [Revised: 12/05/2023] [Accepted: 12/15/2023] [Indexed: 01/27/2024] Open
Abstract
Carvacryl acetate (CA) is a monoterpene obtained from carvacrol, which exhibits anti-inflammatory activity. However, its low solubility in aqueous media limits its application and bioavailability. Herein, we aimed to develop a carvacryl acetate nanoemulsion (CANE) and assess its anti-inflammatory potential in preclinical trials. The optimized nanoemulsion was produced by ultrasound, and stability parameters were characterized for 90 days using dynamic light scattering after hydrophilic-lipophilic balance (HLB) assessment. To evaluate anti-inflammatory activity, a complete Freund's adjuvant-induced inflammation model was established. Paw edema was measured, and local interleukin (IL)-1β levels were quantified using ELISA. Toxicity was assessed based on behavioral changes and biochemical assays. The optimized nanoemulsion contained 3% CA, 9% surfactants (HLB 9), and 88% water and exhibited good stability over 90 days, with no signs of toxicity. The release study revealed that CANE followed zero-order kinetics. Dose-response curves for CA were generated for intraperitoneal and oral administration, demonstrating anti-inflammatory effects by both routes; however, efficacy was lower when administered orally. Furthermore, CANE showed improved anti-inflammatory activity when compared with free oil, particularly when administered orally. Moreover, daily treatment with CANE did not induce behavioral or biochemical alterations. Overall, these findings indicate that nanoemulsification can enhance the anti-inflammatory properties of CA by oral administration.
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Affiliation(s)
- Rafael Limongi de Souza
- Laboratory of Synthesis and Drug Delivery, State University of Paraíba, Rua Horácio Trajano, SN, João Pessoa 58071-160, PB, Brazil
| | - Luíza Carolina França Opretzka
- Laboratório de Farmacologia e Terapêutica Experimental, Faculdade de Farmácia, Universidade Federal da Bahia, Rua Barão de Jeremoabo, 147, Ondina, Salvador 40170-115, BA, Brazil (C.F.V.)
| | - Mayara Castro de Morais
- Department of Pharmaceutical Sciences, Federal University of Paraíba, João Pessoa 58051-970, PB, Brazil (D.P.d.S.)
| | - Camila de Oliveira Melo
- Laboratory of Synthesis and Drug Delivery, State University of Paraíba, Rua Horácio Trajano, SN, João Pessoa 58071-160, PB, Brazil
| | | | - Damião Pergentino de Sousa
- Department of Pharmaceutical Sciences, Federal University of Paraíba, João Pessoa 58051-970, PB, Brazil (D.P.d.S.)
| | - Cristiane Flora Villarreal
- Laboratório de Farmacologia e Terapêutica Experimental, Faculdade de Farmácia, Universidade Federal da Bahia, Rua Barão de Jeremoabo, 147, Ondina, Salvador 40170-115, BA, Brazil (C.F.V.)
| | - Elquio Eleamen Oliveira
- Laboratory of Synthesis and Drug Delivery, State University of Paraíba, Rua Horácio Trajano, SN, João Pessoa 58071-160, PB, Brazil
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14
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Garcia-Puente LM, Fraile-Martinez O, García-Montero C, Bujan J, De León-Luis JA, Bravo C, Rodríguez-Benitez P, Pintado P, Ruiz-Labarta FJ, Álvarez-Mon M, García-Honduvilla N, Cancelo MJ, Saez MA, Ortega MA. Placentas from Women with Late-Onset Preeclampsia Exhibit Increased Expression of the NLRP3 Inflammasome Machinery. Biomolecules 2023; 13:1644. [PMID: 38002326 PMCID: PMC10669618 DOI: 10.3390/biom13111644] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Revised: 11/03/2023] [Accepted: 11/08/2023] [Indexed: 11/26/2023] Open
Abstract
Pre-eclampsia is a harmful and potentially lethal medical condition during pregnancy clinically diagnosed by hypertension and commonly accompanied by proteinuria and multiorgan affections. According to the time of diagnosis, it is differentiated between early-onset (EO-PE) and late-onset preeclampsia (LO-PE). Despite being less dangerous and presenting distinct pathophysiological signatures, LO-PE has a greater prevalence than EO-PE, both having significant consequences on the placenta. Previous works have evidenced that exacerbated inflammation in this organ might play a potential pathogenic role in the development of pre-eclampsia, and there is some preliminary evidence that the hyperactivation of inflammasomes can be related to the altered immunoinflammatory responses observed in the placentas of these patients. However, the precise role of inflammasomes in the placentas of women with LO-PE remains to be fully understood. In this work, we have studied the gene and protein expression of the main components related to the canonical and non-canonical pathways of the inflammasome NLRP3 (NLRP3, ASC, caspase 1, caspase 5, caspase 8, interleukin 1β, and interleukin 18) in the placental tissue of women with LO-PE. Our results show a marked increase in all these components in the placentas of women who have undergone LO-PE, suggesting that NLRP3 inflammasome plays a potentially pathophysiological role in the development of this entity. Future works should aim to evaluate possible translational approaches to this dysregulation in these patients.
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Affiliation(s)
- Luis M Garcia-Puente
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcalá de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
| | - Oscar Fraile-Martinez
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcalá de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
| | - Cielo García-Montero
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcalá de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
| | - Julia Bujan
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcalá de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
| | - Juan A De León-Luis
- Department of Public and Maternal and Child Health, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain
- Department of Obstetrics and Gynecology, University Hospital Gregorio Marañón, 28009 Madrid, Spain
- Health Research Institute Gregorio Marañón, 28009 Madrid, Spain
| | - Coral Bravo
- Department of Public and Maternal and Child Health, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain
- Department of Obstetrics and Gynecology, University Hospital Gregorio Marañón, 28009 Madrid, Spain
- Health Research Institute Gregorio Marañón, 28009 Madrid, Spain
| | - Patrocinio Rodríguez-Benitez
- Department of Public and Maternal and Child Health, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain
- Health Research Institute Gregorio Marañón, 28009 Madrid, Spain
- Department of Nephrology, University Hospital Gregorio Marañón, 28009 Madrid, Spain
| | - Pilar Pintado
- Department of Public and Maternal and Child Health, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain
- Department of Obstetrics and Gynecology, University Hospital Gregorio Marañón, 28009 Madrid, Spain
- Health Research Institute Gregorio Marañón, 28009 Madrid, Spain
| | - Francisco Javier Ruiz-Labarta
- Department of Public and Maternal and Child Health, School of Medicine, Complutense University of Madrid, 28040 Madrid, Spain
- Department of Obstetrics and Gynecology, University Hospital Gregorio Marañón, 28009 Madrid, Spain
- Health Research Institute Gregorio Marañón, 28009 Madrid, Spain
| | - Melchor Álvarez-Mon
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcalá de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
- Immune System Diseases-Rheumatology and Internal Medicine Service, University Hospital Prince of Asturias, Networking Research Center on for Liver and Digestive Diseases (CIBEREHD), 28806 Alcalá de Henares, Spain
| | - Natalio García-Honduvilla
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcalá de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
| | - María J Cancelo
- Department of Surgery, Medical and Social Sciences, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
- Department of Obstetrics and Gynecology, University Hospital of Guadalajara, 19002 Guadalajara, Spain
| | - Miguel A Saez
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcalá de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
- Pathological Anatomy Service, University Hospital Gómez-Ulla, 28806 Alcalá de Henares, Spain
| | - Miguel A Ortega
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcalá de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
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15
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Tsilioni I, Theoharides TC. Recombinant SARS-CoV-2 Spike Protein and Its Receptor Binding Domain Stimulate Release of Different Pro-Inflammatory Mediators via Activation of Distinct Receptors on Human Microglia Cells. Mol Neurobiol 2023; 60:6704-6714. [PMID: 37477768 DOI: 10.1007/s12035-023-03493-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Accepted: 07/10/2023] [Indexed: 07/22/2023]
Abstract
SARS-CoV-2 infects cells via its spike (S) protein binding to its surface receptor angiotensin converting enzyme 2 (ACE2) on target cells and results in acute symptoms involving especially the lungs known as COVID-19. However, increasing evidence indicates that SARS-CoV-2 infection produces neuroinflammation associated with neurological, neuropsychiatric, and cognitive symptoms persists well past the resolution of the infection, known as post-COVID-19 sequalae or long-COVID. The neuroimmune mechanism(s) involved in long-COVID have not been adequately characterized. In this study, we show that recombinant SARS-CoV-2 full-length S protein stimulates release of pro-inflammatory IL-1b, CXCL8, IL-6, and MMP-9 from cultured human microglia via TLR4 receptor activation. Instead, recombinant receptor-binding domain (RBD) stimulates release of TNF-α, IL-18, and S100B via ACE2 signaling. These results provide evidence that SARS-CoV-2 spike protein contributes to neuroinflammation through different mechanisms that may be involved in CNS pathologies associated with long-COVID.
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Affiliation(s)
- Irene Tsilioni
- Laboratory of Molecular Immunopharmacology and Drug Discovery, Department of Immunology, Tufts University School of Medicine, 136 Harrison Avenue, Suite 304, Boston, MA, 02111, USA.
| | - Theoharis C Theoharides
- Laboratory of Molecular Immunopharmacology and Drug Discovery, Department of Immunology, Tufts University School of Medicine, 136 Harrison Avenue, Suite 304, Boston, MA, 02111, USA
- Institute of Neuro-Immune Medicine, Nova Southeastern University, Clearwater, FL, 33759, USA
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16
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Timmerman R, Zuiderwijk-Sick EA, Baron W, Bajramovic JJ. In silico-in vitro modeling to uncover cues involved in establishing microglia identity: TGF-β3 and laminin can drive microglia signature gene expression. Front Cell Neurosci 2023; 17:1178504. [PMID: 37435046 PMCID: PMC10330817 DOI: 10.3389/fncel.2023.1178504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Accepted: 06/12/2023] [Indexed: 07/13/2023] Open
Abstract
Microglia are the resident macrophages of the central nervous system (CNS) and play a key role in CNS development, homeostasis, and disease. Good in vitro models are indispensable to study their cellular biology, and although much progress has been made, in vitro cultures of primary microglia still only partially recapitulate the transcriptome of in vivo microglia. In this study, we explored a combination of in silico and in vitro methodologies to gain insight into cues that are involved in the induction or maintenance of the ex vivo microglia reference transcriptome. First, we used the in silico tool NicheNet to investigate which (CNS-derived) cues could underlie the differences between the transcriptomes of ex vivo and in vitro microglia. Modeling on basis of gene products that were found to be upregulated in vitro, predicted that high mobility group box 2 (HMGB2)- and interleukin (IL)-1β-associated signaling pathways were driving their expression. Modeling on basis of gene products that were found to be downregulated in vitro, did not lead to predictions on the involvement of specific signaling pathways. This is consistent with the idea that in vivo microenvironmental cues that determine microglial identity are for most part of inhibitory nature. In a second approach, primary microglia were exposed to conditioned medium from different CNS cell types. Conditioned medium from spheres composed of microglia, oligodendrocytes, and radial glia, increased the mRNA expression levels of the microglia signature gene P2RY12. NicheNet analyses of ligands expressed by oligodendrocytes and radial glia predicted transforming growth factor beta 3 (TGF-β3) and LAMA2 as drivers of microglia signature gene expression. In a third approach, we exposed microglia to TGF-β3 and laminin. In vitro exposure to TGF-β3 increased the mRNA expression levels of the microglia signature gene TREM2. Microglia cultured on laminin-coated substrates were characterized by reduced mRNA expression levels of extracellular matrix-associated genes MMP3 and MMP7, and by increased mRNA expression levels of the microglia signature genes GPR34 and P2RY13. Together, our results suggest to explore inhibition of HMGB2- and IL-1β-associated pathways in in vitro microglia. In addition, exposure to TGF-β3 and cultivation on laminin-coated substrates are suggested as potential improvements to current in vitro microglia culture protocols.
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Affiliation(s)
- Raissa Timmerman
- Alternatives Unit, Biomedical Primate Research Centre, Rijswijk, Netherlands
| | | | - Wia Baron
- Department of Biomedical Sciences of Cells and Systems, Section Molecular Neurobiology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Jeffrey John Bajramovic
- Alternatives Unit, Biomedical Primate Research Centre, Rijswijk, Netherlands
- 3Rs Centre Utrecht, Utrecht University, Utrecht, Netherlands
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17
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Hédou J, Marić I, Bellan G, Einhaus J, Gaudillière DK, Ladant FX, Verdonk F, Stelzer IA, Feyaerts D, Tsai AS, Ganio EA, Sabayev M, Gillard J, Bonham TA, Sato M, Diop M, Angst MS, Stevenson D, Aghaeepour N, Montanari A, Gaudillière B. Stabl: sparse and reliable biomarker discovery in predictive modeling of high-dimensional omic data. RESEARCH SQUARE 2023:rs.3.rs-2609859. [PMID: 36909508 PMCID: PMC10002850 DOI: 10.21203/rs.3.rs-2609859/v1] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/06/2023]
Abstract
High-content omic technologies coupled with sparsity-promoting regularization methods (SRM) have transformed the biomarker discovery process. However, the translation of computational results into a clinical use-case scenario remains challenging. A rate-limiting step is the rigorous selection of reliable biomarker candidates among a host of biological features included in multivariate models. We propose Stabl, a machine learning framework that unifies the biomarker discovery process with multivariate predictive modeling of clinical outcomes by selecting a sparse and reliable set of biomarkers. Evaluation of Stabl on synthetic datasets and four independent clinical studies demonstrates improved biomarker sparsity and reliability compared to commonly used SRMs at similar predictive performance. Stabl readily extends to double- and triple-omics integration tasks and identifies a sparser and more reliable set of biomarkers than those selected by state-of-the-art early- and late-fusion SRMs, thereby facilitating the biological interpretation and clinical translation of complex multi-omic predictive models. The complete package for Stabl is available online at https://github.com/gregbellan/Stabl.
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Affiliation(s)
- Julien Hédou
- Department of Anesthesiology, Perioperative & Pain Medicine, Stanford University, Stanford, CA
| | - Ivana Marić
- Department of Pediatrics, Stanford University, Stanford, CA
| | | | - Jakob Einhaus
- Department of Anesthesiology, Perioperative & Pain Medicine, Stanford University, Stanford, CA
- Department of Pathology and Neuropathology, University Hospital and Comprehensive Cancer Center Tübingen, Tübingen, Germany
| | - Dyani K. Gaudillière
- Division of Plastic and Reconstructive Surgery, Department of Surgery, Stanford University, Stanford, CA
| | | | - Franck Verdonk
- Department of Anesthesiology, Perioperative & Pain Medicine, Stanford University, Stanford, CA
- Sorbonne University, GRC 29, AP-HP, DMU DREAM, Department of Anesthesiology and Intensive Care, Hôpital Saint-Antoine, Assistance Publique-Hôpitaux de Paris; Paris, France
| | - Ina A. Stelzer
- Department of Anesthesiology, Perioperative & Pain Medicine, Stanford University, Stanford, CA
| | - Dorien Feyaerts
- Department of Anesthesiology, Perioperative & Pain Medicine, Stanford University, Stanford, CA
| | - Amy S. Tsai
- Department of Anesthesiology, Perioperative & Pain Medicine, Stanford University, Stanford, CA
| | - Edward A. Ganio
- Department of Anesthesiology, Perioperative & Pain Medicine, Stanford University, Stanford, CA
| | - Maximilian Sabayev
- Department of Anesthesiology, Perioperative & Pain Medicine, Stanford University, Stanford, CA
| | - Joshua Gillard
- Department of Anesthesiology, Perioperative & Pain Medicine, Stanford University, Stanford, CA
| | - Thomas A. Bonham
- Department of Anesthesiology, Perioperative & Pain Medicine, Stanford University, Stanford, CA
| | - Masaki Sato
- Department of Anesthesiology, Perioperative & Pain Medicine, Stanford University, Stanford, CA
| | - Maïgane Diop
- Department of Anesthesiology, Perioperative & Pain Medicine, Stanford University, Stanford, CA
| | - Martin S. Angst
- Department of Anesthesiology, Perioperative & Pain Medicine, Stanford University, Stanford, CA
| | | | - Nima Aghaeepour
- Department of Anesthesiology, Perioperative & Pain Medicine, Stanford University, Stanford, CA
- Department of Pediatrics, Stanford University, Stanford, CA
- Department of Biomedical Data Science, Stanford University, Stanford, CA
| | - Andrea Montanari
- Department of Statistics, Stanford University, Stanford, CA
- Department of Electrical Engineering, Stanford University, Stanford, CA
| | - Brice Gaudillière
- Department of Anesthesiology, Perioperative & Pain Medicine, Stanford University, Stanford, CA
- Department of Pediatrics, Stanford University, Stanford, CA
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18
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Miyazaki T, Taketomi Y, Higashi T, Ohtaki H, Takaki T, Ohnishi K, Hosonuma M, Kono N, Akasu R, Haraguchi S, Kim-Kaneyama JR, Otsu K, Arai H, Murakami M, Miyazaki A. Hypercholesterolemic Dysregulation of Calpain in Lymphatic Endothelial Cells Interferes With Regulatory T-Cell Stability and Trafficking. Arterioscler Thromb Vasc Biol 2023; 43:e66-e82. [PMID: 36519468 DOI: 10.1161/atvbaha.122.317781] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 11/29/2022] [Indexed: 12/23/2022]
Abstract
BACKGROUND Although hypercholesterolemia reportedly counteracts lymphocyte trafficking across lymphatic vessels, the roles of lymphatic endothelial cells (LECs) in the lymphocyte regulations remain unclear. Previous studies showed that calpain-an intracellular modulatory protease-interferes with leukocyte dynamics in the blood microcirculation and is associated with hypercholesterolemic dysfunction in vascular endothelial cells. METHODS This study investigated whether the calpain systems in LECs associate with the LEC-lymphocyte interaction under hypercholesterolemia using gene-targeted mice. RESULTS Lipidomic analysis in hypercholesterolemic mice showed that several lysophospholipids, including lysophosphatidic acid, accumulated in the lymphatic environment. Lysophosphatidic acid enables the potentiation of calpain systems in cultured LECs, which limits their ability to stabilize regulatory T cells (Treg) without altering Th1/Th2 (T helper type1/2) subsets. This occurs via the proteolytic degradation of MEKK1 (mitogen-activated protein kinase kinase kinase 1) and the subsequent inhibition of TGF (transforming growth factor)-β1 production in LECs. Targeting calpain systems in LECs expanded Tregs in the blood circulation and reduced aortic atherosclerosis in hypercholesterolemic mice, concomitant with the reduction of proinflammatory macrophages in the lesions. Treg expansion in the blood circulation and atheroprotection in calpain-targeted mice was prevented by the administration of TGF-β type-I receptor inhibitor. Moreover, lysophosphatidic acid-induced calpain overactivation potentiated the IL (interleukin)-18/NF-κB (nuclear factor κB)/VCAM1 (vascular cell adhesion molecule 1) axis in LECs, thereby inhibiting lymphocyte mobility on the cells. Indeed, VCAM1 in LECs was upregulated in hypercholesterolemic mice and human cases of coronary artery disease. Neutralization of VCAM1 or targeting LEC calpain systems recovered afferent Treg transportation via lymphatic vessels in mice. CONCLUSIONS Calpain systems in LECs have a key role in controlling Treg stability and trafficking under hypercholesterolemia.
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Affiliation(s)
- Takuro Miyazaki
- Department of Biochemistry (T.M., R.A., S.H., J.-R.K.-K., A.M.), Showa University School of Medicine, Tokyo, Japan
| | - Yoshitaka Taketomi
- Laboratory of Microenvironmental and Metabolic Health Science, Center for Disease Biology and Integrative Medicine (Y.T., T.H., M.M.), the University of Tokyo, Japan
| | - Takayoshi Higashi
- Laboratory of Microenvironmental and Metabolic Health Science, Center for Disease Biology and Integrative Medicine (Y.T., T.H., M.M.), the University of Tokyo, Japan
| | - Hirokazu Ohtaki
- Department of Anatomy (H.O.), Showa University School of Medicine, Tokyo, Japan
| | - Takashi Takaki
- Division of Electron Microscopy (T.T.), Showa University School of Medicine, Tokyo, Japan
| | - Koji Ohnishi
- Department of Pathology, Aichi Medical University School of Medicine, Nagakute, Japan (K. Ohnishi)
| | - Masahiro Hosonuma
- Department of Clinical Immuno Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa University, Tokyo, Japan (M.H.)
| | - Nozomu Kono
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Graduate School of Medicine (N.K., H.A.), the University of Tokyo, Japan
| | - Risako Akasu
- Department of Biochemistry (T.M., R.A., S.H., J.-R.K.-K., A.M.), Showa University School of Medicine, Tokyo, Japan
| | - Shogo Haraguchi
- Department of Biochemistry (T.M., R.A., S.H., J.-R.K.-K., A.M.), Showa University School of Medicine, Tokyo, Japan
| | - Joo-Ri Kim-Kaneyama
- Department of Biochemistry (T.M., R.A., S.H., J.-R.K.-K., A.M.), Showa University School of Medicine, Tokyo, Japan
| | - Kinya Otsu
- The School of Cardiovascular Medicine and Sciences, King's College London British Heart Foundation Centre of Excellence, London, United Kingdom (K. Otsu)
| | - Hiroyuki Arai
- Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Graduate School of Medicine (N.K., H.A.), the University of Tokyo, Japan
| | - Makoto Murakami
- Laboratory of Microenvironmental and Metabolic Health Science, Center for Disease Biology and Integrative Medicine (Y.T., T.H., M.M.), the University of Tokyo, Japan
| | - Akira Miyazaki
- Department of Biochemistry (T.M., R.A., S.H., J.-R.K.-K., A.M.), Showa University School of Medicine, Tokyo, Japan
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19
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Rai S, Grockowiak E, Hansen N, Luque Paz D, Stoll CB, Hao-Shen H, Mild-Schneider G, Dirnhofer S, Farady CJ, Méndez-Ferrer S, Skoda RC. Inhibition of interleukin-1β reduces myelofibrosis and osteosclerosis in mice with JAK2-V617F driven myeloproliferative neoplasm. Nat Commun 2022; 13:5346. [PMID: 36100613 PMCID: PMC9470591 DOI: 10.1038/s41467-022-32927-4] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 08/24/2022] [Indexed: 12/17/2022] Open
Abstract
Interleukin-1β (IL-1β) is a master regulator of inflammation. Increased activity of IL-1β has been implicated in various pathological conditions including myeloproliferative neoplasms (MPNs). Here we show that IL-1β serum levels and expression of IL-1 receptors on hematopoietic progenitors and stem cells correlate with JAK2-V617F mutant allele fraction in peripheral blood of patients with MPN. We show that the source of IL-1β overproduction in a mouse model of MPN are JAK2-V617F expressing hematopoietic cells. Knockout of IL-1β in hematopoietic cells of JAK2-V617F mice reduces inflammatory cytokines, prevents damage to nestin-positive niche cells and reduces megakaryopoiesis, resulting in decrease of myelofibrosis and osteosclerosis. Inhibition of IL-1β in JAK2-V617F mutant mice by anti-IL-1β antibody also reduces myelofibrosis and osteosclerosis and shows additive effects with ruxolitinib. These results suggest that inhibition of IL-1β with anti-IL-1β antibody alone or in combination with ruxolitinib could have beneficial effects on the clinical course in patients with myelofibrosis.
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Affiliation(s)
- Shivam Rai
- Department of Biomedicine, Experimental Hematology, University Hospital Basel, University of Basel, 4031, Basel, Switzerland
| | - Elodie Grockowiak
- Wellcome-MRC Cambridge Stem Cell Institute, Cambridge, CB2 0AW, UK
- Department of Hematology, University of Cambridge, Cambridge, CB2 0AW, UK
- National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, CB2 0AW, UK
| | - Nils Hansen
- Department of Biomedicine, Experimental Hematology, University Hospital Basel, University of Basel, 4031, Basel, Switzerland
| | - Damien Luque Paz
- Department of Biomedicine, Experimental Hematology, University Hospital Basel, University of Basel, 4031, Basel, Switzerland
| | - Cedric B Stoll
- Department of Biomedicine, Experimental Hematology, University Hospital Basel, University of Basel, 4031, Basel, Switzerland
| | - Hui Hao-Shen
- Department of Biomedicine, Experimental Hematology, University Hospital Basel, University of Basel, 4031, Basel, Switzerland
| | - Gabriele Mild-Schneider
- Department of Biomedicine, Experimental Hematology, University Hospital Basel, University of Basel, 4031, Basel, Switzerland
| | - Stefan Dirnhofer
- Department of Pathology, University Hospital Basel, 4031, Basel, Switzerland
| | | | - Simón Méndez-Ferrer
- Wellcome-MRC Cambridge Stem Cell Institute, Cambridge, CB2 0AW, UK
- Department of Hematology, University of Cambridge, Cambridge, CB2 0AW, UK
- National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, CB2 0AW, UK
| | - Radek C Skoda
- Department of Biomedicine, Experimental Hematology, University Hospital Basel, University of Basel, 4031, Basel, Switzerland.
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20
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Zhang J, Wirtz S. Does Pyroptosis Play a Role in Inflammasome-Related Disorders? Int J Mol Sci 2022; 23:ijms231810453. [PMID: 36142364 PMCID: PMC9499396 DOI: 10.3390/ijms231810453] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 08/22/2022] [Accepted: 09/06/2022] [Indexed: 11/30/2022] Open
Abstract
Inflammasomes are multiprotein complexes orchestrating intracellular recognition of endogenous and exogenous stimuli, cellular homeostasis, and cell death. Upon sensing of certain stimuli, inflammasomes typically activate inflammatory caspases that promote the production and release of the proinflammatory cytokines IL-1β, IL-1α, and IL-18 and induce a type of inflammatory cell death known as “pyroptosis”. Pyroptosis is an important form of regulated cell death executed by gasdermin proteins, which is largely different from apoptosis and necrosis. Recently, several signaling pathways driving pyroptotic cell death, including canonical and noncanonical inflammasome activation, as well as caspase-3-dependent pathways, have been reported. While much evidence exists that pyroptosis is involved in the development of several inflammatory diseases, its contribution to inflammasome-related disorders (IRDs) has not been fully clarified. This article reviews molecular mechanisms leading to pyroptosis, and attempts to provide evidence for its possible role in inflammasome-related disorders, including NLR pyrin domain containing 3 (NLRP3) inflammasome disease, NLR containing a caspase recruitment domain 4 (NLRC4) inflammasome disease, and pyrin inflammasome disease. Although the specific mechanism needs further investigations, these studies have uncovered the role of pyroptosis in inflammasome-related disorders and may open new avenues for future therapeutic interventions.
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Affiliation(s)
- Jiajia Zhang
- Medizinische Klinik 1, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91052 Erlangen, Germany
| | - Stefan Wirtz
- Medizinische Klinik 1, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91052 Erlangen, Germany
- Medical Immunology Campus Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91052 Erlangen, Germany
- Correspondence:
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21
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IL-18 Signaling Is Essential for Causing Streptococcal Toxic Shock-like Syndrome (STSLS). Life (Basel) 2022; 12:life12091324. [PMID: 36143361 PMCID: PMC9503922 DOI: 10.3390/life12091324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 08/09/2022] [Accepted: 08/24/2022] [Indexed: 11/16/2022] Open
Abstract
Streptococcus suis (S. suis) is an emerging zoonotic pathogen that can cause multiple diseases, including streptococcal toxic shock-like syndrome (STSLS). The S. suis SC-19 strain could cause NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome hyperactivation, then induce a cytokine storm and STSLS. Although IL-18 is the downstream effector of NLRP3 signaling, the role of IL-18 signaling on STSLS remains to be elucidated. Thus, il18r1 gene knockout mice were constructed and challenged with the SC-19 strain. Alleviated clinical signs and tissue damages, as well as improved survival were observed in il18r−/− mice compared with the WT mice post-SC-19 challenge. Meanwhile, an obvious decrease in the inflammatory cytokine levels in blood was observed in the il18r-/- mice infected with SC-19. Therefore, IL-18, the downstream effector of NLRP3 inflammasome activation, was responsible for the cytokine storm and STSLS development caused by S. suis, suggesting that IL-18/IL-18Rα signaling could serve as a new target for STSLS.
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22
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Xu Y, Li P, Li K, Li N, Liu H, Zhang X, Liu W, Liu Y. Pathological mechanisms and crosstalk among different forms of cell death in systemic lupus erythematosus. J Autoimmun 2022; 132:102890. [PMID: 35963809 DOI: 10.1016/j.jaut.2022.102890] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2022] [Accepted: 07/29/2022] [Indexed: 10/15/2022]
Abstract
Systemic lupus erythematosus (SLE) is a systemic autoimmune disorder characterized by a profound immune dysregulation and the presence of a variety of autoantibodies. Aberrant activation of programmed cell death (PCD) signaling and accelerated cell death is critical in the immunopathogenesis of SLE. Accumulating cellular components from the dead cells and ineffective clearance of the dead cell debris, in particular the nucleic acids and nucleic acids-protein complexes, provide a stable source of self-antigens, which potently activate auto-reactive B cells and promote IFN-I responses in SLE. Different cell types display distinct susceptibility and characteristics to a certain type of cell death, while different PCDs in various cells have mutual and intricate connections to promote immune dysregulation and contribute to the development of SLE. In this review, we discuss the role of various cell death pathways and their interactions in the pathogenesis of SLE. An in depth understanding of the interconnections among various forms cell death in SLE will lead to a better understanding of disease pathogenesis, shedding light on the development of novel therapeutic targets.
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Affiliation(s)
- Yue Xu
- Department of Rheumatology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Pengchong Li
- Department of Gastroenterology, Beijing Friendship Hospital, National Clinical Research Center for Digestive Diseases, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, Capital Medical University, Beijing, China
| | - Ketian Li
- Department of Rheumatology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Nannan Li
- Department of Rheumatology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Huazhen Liu
- Peking Union Medical College Hospital, Beijing, China
| | - Xuan Zhang
- Department of Rheumatology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Wei Liu
- Department of Rheumatology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China.
| | - Yudong Liu
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, 100730, China.
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23
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Zhang HQ, Yang SW, Fu YC, Chen MC, Yang CH, Yang MH, Liu XD, He QN, Jiang H, Zhao MY. Cytokine storm and targeted therapy in hemophagocytic lymphohistiocytosis. Immunol Res 2022; 70:566-577. [PMID: 35819695 DOI: 10.1007/s12026-022-09285-w] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 05/03/2022] [Indexed: 11/05/2022]
Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening systemic hyperinflammatory syndrome. The central pathogenesis is an explosive cytokine storm characterized by a significant increase in proinflammatory cytokines, including IL-1β, IL-6, IL-18, IFN-γ, and TNF-α. Meanwhile, negative regulatory factors, such as IL-10 and TGF-β, are also related to the production of HLH. Exploring the specific mechanism of cytokine storms could provide ideas regarding targeted therapy, which could be helpful for early treatment to reduce the mortality of HLH. Although some research has focused on the advantages of targeted therapies, there is still a lack of a comprehensive discourse. This article attempts to summarize the mechanisms of action of various cytokines and provide a therapeutic overview of the current targeted therapies for HLH.
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Affiliation(s)
- Han-Qi Zhang
- Department of Pediatrics, The Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China.,Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Si-Wei Yang
- Department of Pediatrics, The Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China.,Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Yi-Cheng Fu
- Department of Pediatrics, The Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China
| | - Ming-Cong Chen
- Department of Pediatrics, The Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China
| | - Cheng-Hao Yang
- Department of Pediatrics, The Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China.,Xiangya School of Medicine, Central South University, Changsha, 410013, Hunan, China
| | - Ming-Hua Yang
- Department of Pediatrics, The Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China
| | - Xiao-Dan Liu
- Department of Hematology/Oncology, Guangzhou Women and Children's Medical Center, Guangzhou, 510623, Guangdong, China
| | - Qing-Nan He
- Department of Pediatrics, The Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China.
| | - Hua Jiang
- Department of Hematology/Oncology, Guangzhou Women and Children's Medical Center, Guangzhou, 510623, Guangdong, China.
| | - Ming-Yi Zhao
- Department of Pediatrics, The Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China.
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You R, He X, Zeng Z, Zhan Y, Xiao Y, Xiao R. Pyroptosis and Its Role in Autoimmune Disease: A Potential Therapeutic Target. Front Immunol 2022; 13:841732. [PMID: 35693810 PMCID: PMC9174462 DOI: 10.3389/fimmu.2022.841732] [Citation(s) in RCA: 59] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 04/29/2022] [Indexed: 12/13/2022] Open
Abstract
Autoimmune diseases are a group of heterogeneous diseases with diverse clinical manifestations that can be divided into systemic and organ-specific. The common etiology of autoimmune diseases is the destruction of immune tolerance and the production of autoantibodies, which attack specific tissues and/or organs in the body. The pathogenesis of autoimmune diseases is complicated, and genetic, environmental, infectious, and even psychological factors work together to cause aberrant innate and adaptive immune responses. Although the exact mechanisms are unclear, recently, excessive exacerbation of pyroptosis, as a bond between innate and adaptive immunity, has been proven to play a crucial role in the development of autoimmune disease. Pyroptosis is characterized by pore formation on cell membranes, as well as cell rupture and the excretion of intracellular contents and pro-inflammatory cytokines, such as IL-1β and IL-18. This overactive inflammatory programmed cell death disrupts immune system homeostasis and promotes autoimmunity. This review examines the molecular structure of classical inflammasomes, including NLRP3, AIM2, and P2X7-NLRP3, as the switches of pyroptosis, and their molecular regulation mechanisms. The sophisticated pyroptosis pathways, including the canonical caspase-1-mediated pathway, the noncanonical caspase-4/5/11-mediated pathway, the emerging caspase-3-mediated pathway, and the caspase-independent pathway, are also described. We highlight the recent advances in pyroptosis in autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, Sjögren's syndrome and dermatomyositis, and attempt to identify its potential advantages as a therapeutic target or prognostic marker in these diseases.
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Affiliation(s)
- Ruixuan You
- Department of Dermatology, The Second Xiangya Hospital of Central South University, Changsha, China.,Hunan Key Laboratory of Medical Epigenetics, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Xinglan He
- Department of Dermatology, The Second Xiangya Hospital of Central South University, Changsha, China.,Hunan Key Laboratory of Medical Epigenetics, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Zhuotong Zeng
- Department of Dermatology, The Second Xiangya Hospital of Central South University, Changsha, China.,Hunan Key Laboratory of Medical Epigenetics, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Yi Zhan
- Department of Dermatology, The Second Xiangya Hospital of Central South University, Changsha, China.,Hunan Key Laboratory of Medical Epigenetics, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Yangfan Xiao
- Clinical Nursing Teaching and Research Section, The Second Xiangya Hospital of Central South University, Changsha, China.,Department of Anesthesiology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Rong Xiao
- Department of Dermatology, The Second Xiangya Hospital of Central South University, Changsha, China.,Hunan Key Laboratory of Medical Epigenetics, The Second Xiangya Hospital of Central South University, Changsha, China
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25
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Miller AS, Hidalgo TN, Abrahams VM. Human fetal membrane IL-1β production in response to bacterial components is mediated by uric-acid induced NLRP3 inflammasome activation. J Reprod Immunol 2022; 149:103457. [PMID: 34875574 PMCID: PMC8792319 DOI: 10.1016/j.jri.2021.103457] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 11/05/2021] [Accepted: 11/24/2021] [Indexed: 02/03/2023]
Abstract
Inflammatory interleukin-1β (IL-1β) is an important mediator of preterm birth. IL-1β secretion is mediated by the inflammasome that processes pro-IL-1β into its active form. However the mechanisms involved at the level of the fetal membrane (FM) are not fully understood. This study sought to determine the FM compartment involved in IL-1β production in response to bacterial components and to evaluate the mechanism of inflammasome activation. Since IL-18 is also mediated by the inflammasome and IL-8 is a chemoattractant that contributes to neutrophil recruitment in chorioamnionitis, we also evaluated the production of these factors. A human explant system was used to evaluate the response of the chorion, amnion, and intact FMs to the bacterial components lipopolysaccharide (LPS), peptidoglycan (PGN), or muramyl dipeptide (MDP). The chorion was the major source of IL-1β and IL-8 production in response to LPS, PGN, and MDP. LPS, PGN, and MDP induced FM IL-1β and IL-18 secretion in a non-pyroptotic manner through activation of the NLRP3 inflammasome with contributions from ATP release through Pannexin-1, and ROS signaling. Since LPS, PGN, and MDP are not known to activate NLRP3 directly, the role of uric acid as a potential mediator was assessed. FMs produced elevated uric acid in response to LPS, PGN and MDP. FM IL-1β secretion was inhibited by allopurinol, which blocks uric acid production, for LPS and PGN, and to a lesser degree, MDP. These findings shed light on the mechanisms by which fetal membrane inflammation and subsequent preterm birth may arise.
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Affiliation(s)
- Alex S. Miller
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT
| | - Tiffany N. Hidalgo
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT
| | - Vikki M. Abrahams
- Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, New Haven, CT,Corresponding Author: Vikki M. Abrahams PhD. Department of Obstetrics, Gynecology & Reproductive Sciences, Yale School of Medicine, 310 Cedar Street, LSOG 305C, New Haven, CT 06510, USA. ; Phone: 203-785-2175
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26
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Harel M, Fauteux-Daniel S, Girard-Guyonvarc'h C, Gabay C. Balance between Interleukin-18 and Interleukin-18 binding protein in auto-inflammatory diseases. Cytokine 2022; 150:155781. [DOI: 10.1016/j.cyto.2021.155781] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2021] [Accepted: 12/03/2021] [Indexed: 02/07/2023]
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Mathew DJ, Livne-Bar I, Sivak JM. An inducible rodent glaucoma model that exhibits gradual sustained increase in intraocular pressure with distinct inner retina and optic nerve inflammation. Sci Rep 2021; 11:22880. [PMID: 34819548 PMCID: PMC8613281 DOI: 10.1038/s41598-021-02057-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 11/09/2021] [Indexed: 01/29/2023] Open
Abstract
Glaucoma is a chronic and progressive neurodegenerative disease of the optic nerve resulting in loss of retinal ganglion cells (RGCs) and vision. The most prominent glaucoma risk factor is increased intraocular pressure (IOP), and most models focus on reproducing this aspect to study disease mechanisms and targets. Yet, current models result in IOP profiles that often do not resemble clinical glaucoma. Here we introduce a new model that results in a gradual and sustained IOP increase over time. This approach modifies a circumlimbal suture method, taking care to make the sutures 'snug' instead of tight, without inducing an initial IOP spike. This approach did not immediately affect IOPs, but generated gradual ocular hypertension (gOHT) as the sutures tighten over time, in comparison to loosely sutured control eyes (CON), resulting in an average 12.6 mmHg increase in IOP at 17 weeks (p < 0.001). Corresponding characterization revealed relevant retinal and optic nerve pathology, such as thinning of the retinal nerve fiber layer, decreased optokinetic response, RGC loss, and optic nerve head remodeling. Yet, angles remained open, with no evidence of inflammation. Corresponding biochemical profiling indicated significant increases in TGF-β2 and 3, and IL-1 family cytokines in gOHT optic nerve tissues compared to CON, with accompanying microglial reactivity, consistent with active tissue injury and repair mechanisms. Remarkably, this signature was absent from optic nerves following acute ocular hypertension (aOHT) associated with intentionally tightened sutures, although the resulting RGC loss was similar in both methods. These results suggest that the pattern of IOP change has an important impact on underlying pathophysiology.
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Affiliation(s)
- David J Mathew
- Donald K. Johnson Eye Institute, Krembil Research Institute, University Health Network, Toronto, ON, Canada
- Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, ON, Canada
- Department of Lab Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Izhar Livne-Bar
- Donald K. Johnson Eye Institute, Krembil Research Institute, University Health Network, Toronto, ON, Canada
- Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, ON, Canada
- Department of Lab Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Jeremy M Sivak
- Donald K. Johnson Eye Institute, Krembil Research Institute, University Health Network, Toronto, ON, Canada.
- Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, ON, Canada.
- Department of Lab Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
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28
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Liu S, Lai H, Wang Q, Martínez R, Zhang M, Liu Y, Huang J, Deng M, Tu W. Immunotoxicity of F53B, an alternative to PFOS, on zebrafish (Danio rerio) at different early life stages. THE SCIENCE OF THE TOTAL ENVIRONMENT 2021; 790:148165. [PMID: 34380241 DOI: 10.1016/j.scitotenv.2021.148165] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 05/23/2021] [Accepted: 05/27/2021] [Indexed: 06/13/2023]
Abstract
As an alternative to perfluorooctane sulfonate (PFOS), 6:2 chlorinated polyfluorinated ether sulfonate (F53B) has emerged in the Chinese market in recent years and has been frequently detected in the aquatic environment, but its ecological risk assessment is limited. In this study, zebrafish embryos and larvae were separately exposed to F53B, and their 96-h LC50 values were estimated to be 15.1 mg/L and 2.4 mg/L, respectively, suggesting that embryos were more resistant to F53B than larvae. The bioconcentration factor in larvae was basically higher than that of embryos, and the body growth of larvae was significantly affected by F53B rather than embryos, indicating that F53B may cause more severe toxicity to larvae. In addition to the excessive production of ROS and NO, the expression of many immune-related genes was increased in both embryos and larvae, but the number of dysregulated genes in larvae was more than that in embryos. Finally, the results of Point of Departure (PoD) indicated that the immunotoxicity of F53B was more sensitive to larvae than embryos at the molecular level. Our findings revealed the ecological risk of F53B by exploring the adverse effects of immunoregulation at different early life stages of zebrafish and indicated that the zebrafish larvae were more sensitive than embryos.
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Affiliation(s)
- Shuai Liu
- Research Institute of Poyang Lake, Jiangxi Academy of Sciences, Nanchang 330012, China
| | - Hong Lai
- Research Institute of Poyang Lake, Jiangxi Academy of Sciences, Nanchang 330012, China
| | - Qiyu Wang
- Research Institute of Poyang Lake, Jiangxi Academy of Sciences, Nanchang 330012, China
| | - Rubén Martínez
- Department of Cellular Biology, Physiology and Immunology, Universitat de Barcelona (UB), Barcelona, Spain
| | - Miao Zhang
- Research Institute of Poyang Lake, Jiangxi Academy of Sciences, Nanchang 330012, China
| | - Yu Liu
- Research Institute of Poyang Lake, Jiangxi Academy of Sciences, Nanchang 330012, China
| | - Jing Huang
- Research Institute of Poyang Lake, Jiangxi Academy of Sciences, Nanchang 330012, China
| | - Mi Deng
- Research Institute of Poyang Lake, Jiangxi Academy of Sciences, Nanchang 330012, China
| | - Wenqing Tu
- Research Institute of Poyang Lake, Jiangxi Academy of Sciences, Nanchang 330012, China.
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29
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Ren Y, Jiang J, Jiang W, Zhou X, Lu W, Wang J, Luo Y. Spata2 Knockdown Exacerbates Brain Inflammation via NF-κB/P38MAPK Signaling and NLRP3 Inflammasome Activation in Cerebral Ischemia/Reperfusion Rats. Neurochem Res 2021; 46:2262-2275. [PMID: 34075523 DOI: 10.1007/s11064-021-03360-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 05/13/2021] [Accepted: 05/21/2021] [Indexed: 12/27/2022]
Abstract
Brain inflammation induced by ischemic stroke is an important cause of secondary brain injury. The nuclear factor kappa B (NF-κB), mitogen-activated protein kinase (MAPK), and NLRP3 inflammasome signaling are believed to drive the progression of brain inflammation. Spermatogenesis-associated protein2 (SPATA2) functions as a partner protein that recruits CYLD, a negative regulator of NF-κB signaling, to signaling complexes. However, the role of SPATA2 in the central nervous system remains unclear and whether it is involved in regulating inflammatory responses remains controversial. Rats were subjected to transient middle cerebral artery occlusion followed by reperfusion (tMCAO/R) surgery. The expression and localization of SPATA2 in the brain were investigated. The lentivirus-mediated shRNA was employed to inhibit SPATA2 expression. The inflammatory responses and outcomes of Spata2 knockdown were investigated. SPATA2 was co-localized with CYLD in neurons. SPATA2 expression was reduced in tMCAO/R rats. Spata2 knockdown resulted in increased microglia, increased expression of Tnfa, Il-1β, and Il-18, decreased Garcia score, and increased infarct volume. Spata2 knockdown resulted in the activation of P38MAPK and NLRP3 inflammasome and the increased activation of NF-κB signaling. These results suggest that SPATA2 plays a protective role against brain inflammation induced by ischemia/reperfusion injury. Therefore, SPATA2 could be a potential therapeutic target for treating ischemic stroke.
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Affiliation(s)
- Yikun Ren
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
- Laboratory Research Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Jin Jiang
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
- Laboratory Research Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Wenxia Jiang
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
- Laboratory Research Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Xueling Zhou
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
- Laboratory Research Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Wenhao Lu
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
- Laboratory Research Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Jingwen Wang
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
- Laboratory Research Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Yong Luo
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
- Laboratory Research Center, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
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30
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Niklander SE, Murdoch C, Hunter KD. IL-1/IL-1R Signaling in Head and Neck Cancer. FRONTIERS IN ORAL HEALTH 2021; 2:722676. [PMID: 35048046 PMCID: PMC8757896 DOI: 10.3389/froh.2021.722676] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Accepted: 08/04/2021] [Indexed: 01/22/2023] Open
Abstract
Decades ago, the study of cancer biology was mainly focused on the tumor itself, paying little attention to the tumor microenvironment (TME). Currently, it is well recognized that the TME plays a vital role in cancer development and progression, with emerging treatment strategies focusing on different components of the TME, including tumoral cells, blood vessels, fibroblasts, senescent cells, inflammatory cells, inflammatory factors, among others. There is a well-accepted relationship between chronic inflammation and cancer development. Interleukin-1 (IL-1), a potent pro-inflammatory cytokine commonly found at tumor sites, is considered one of the most important inflammatory factors in cancer, and has been related with carcinogenesis, tumor growth and metastasis. Increasing evidence has linked development of head and neck squamous cell carcinoma (HNSCC) with chronic inflammation, and particularly, with IL-1 signaling. This review focuses on the most important members of the IL-1 family, with emphasis on how their aberrant expression can promote HNSCC development and metastasis, highlighting possible clinical applications.
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Affiliation(s)
- Sven E. Niklander
- Unidad de Patología y Medicina Oral, Facultad de Odontologia, Universidad Andres Bello, Viña del Mar, Chile
| | - Craig Murdoch
- Unit of Oral and Maxillofacial Medicine, Pathology and Surgery, School of Clinical Dentistry, University of Sheffield, Sheffield, United Kingdom
| | - Keith D. Hunter
- Unit of Oral and Maxillofacial Medicine, Pathology and Surgery, School of Clinical Dentistry, University of Sheffield, Sheffield, United Kingdom
- Oral Biology and Pathology, University of Pretoria, Pretoria, South Africa
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31
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Molnar V, Matišić V, Kodvanj I, Bjelica R, Jeleč Ž, Hudetz D, Rod E, Čukelj F, Vrdoljak T, Vidović D, Starešinić M, Sabalić S, Dobričić B, Petrović T, Antičević D, Borić I, Košir R, Zmrzljak UP, Primorac D. Cytokines and Chemokines Involved in Osteoarthritis Pathogenesis. Int J Mol Sci 2021; 22:9208. [PMID: 34502117 PMCID: PMC8431625 DOI: 10.3390/ijms22179208] [Citation(s) in RCA: 283] [Impact Index Per Article: 70.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 08/15/2021] [Accepted: 08/24/2021] [Indexed: 12/27/2022] Open
Abstract
Osteoarthritis is a common cause of disability worldwide. Although commonly referred to as a disease of the joint cartilage, osteoarthritis affects all joint tissues equally. The pathogenesis of this degenerative process is not completely understood; however, a low-grade inflammation leading to an imbalance between anabolic and katabolic processes is a well-established factor. The complex network of cytokines regulating these processes and cell communication has a central role in the development and progression of osteoarthritis. Concentrations of both proinflammatory and anti-inflammatory cytokines were found to be altered depending on the osteoarthritis stage and activity. In this review, we analyzed individual cytokines involved in the immune processes with an emphasis on their function in osteoarthritis.
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Affiliation(s)
- Vilim Molnar
- St. Catherine Specialty Hospital, 49210 Zabok, Croatia; (V.M.); (V.M.); (R.B.); (Ž.J.); (D.H.); (E.R.); (F.Č.); (T.V.); (D.V.); (B.D.); (T.P.); (D.A.); (I.B.)
- St. Catherine Specialty Hospital, 10000 Zagreb, Croatia
- Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
| | - Vid Matišić
- St. Catherine Specialty Hospital, 49210 Zabok, Croatia; (V.M.); (V.M.); (R.B.); (Ž.J.); (D.H.); (E.R.); (F.Č.); (T.V.); (D.V.); (B.D.); (T.P.); (D.A.); (I.B.)
- St. Catherine Specialty Hospital, 10000 Zagreb, Croatia
| | - Ivan Kodvanj
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia;
| | - Roko Bjelica
- St. Catherine Specialty Hospital, 49210 Zabok, Croatia; (V.M.); (V.M.); (R.B.); (Ž.J.); (D.H.); (E.R.); (F.Č.); (T.V.); (D.V.); (B.D.); (T.P.); (D.A.); (I.B.)
- St. Catherine Specialty Hospital, 10000 Zagreb, Croatia
| | - Željko Jeleč
- St. Catherine Specialty Hospital, 49210 Zabok, Croatia; (V.M.); (V.M.); (R.B.); (Ž.J.); (D.H.); (E.R.); (F.Č.); (T.V.); (D.V.); (B.D.); (T.P.); (D.A.); (I.B.)
- St. Catherine Specialty Hospital, 10000 Zagreb, Croatia
- Department of Nursing, University North, 48000 Varaždin, Croatia
| | - Damir Hudetz
- St. Catherine Specialty Hospital, 49210 Zabok, Croatia; (V.M.); (V.M.); (R.B.); (Ž.J.); (D.H.); (E.R.); (F.Č.); (T.V.); (D.V.); (B.D.); (T.P.); (D.A.); (I.B.)
- St. Catherine Specialty Hospital, 10000 Zagreb, Croatia
- Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
- Department of Orthopaedic Surgery, Clinical Hospital “Sveti Duh”, 10000 Zagreb, Croatia
| | - Eduard Rod
- St. Catherine Specialty Hospital, 49210 Zabok, Croatia; (V.M.); (V.M.); (R.B.); (Ž.J.); (D.H.); (E.R.); (F.Č.); (T.V.); (D.V.); (B.D.); (T.P.); (D.A.); (I.B.)
- St. Catherine Specialty Hospital, 10000 Zagreb, Croatia
| | - Fabijan Čukelj
- St. Catherine Specialty Hospital, 49210 Zabok, Croatia; (V.M.); (V.M.); (R.B.); (Ž.J.); (D.H.); (E.R.); (F.Č.); (T.V.); (D.V.); (B.D.); (T.P.); (D.A.); (I.B.)
- St. Catherine Specialty Hospital, 10000 Zagreb, Croatia
- University Hospital “Sisters of Mercy”, Clinic for Traumatology, Draškovićeva 19, 10000 Zagreb, Croatia;
- Department of Health Studies, University of Split, 21000 Split, Croatia
- Department of Traumatology, Medical University Merkur Hospital, 10000 Zagreb, Croatia
| | - Trpimir Vrdoljak
- St. Catherine Specialty Hospital, 49210 Zabok, Croatia; (V.M.); (V.M.); (R.B.); (Ž.J.); (D.H.); (E.R.); (F.Č.); (T.V.); (D.V.); (B.D.); (T.P.); (D.A.); (I.B.)
- St. Catherine Specialty Hospital, 10000 Zagreb, Croatia
- Department of Orthopaedic Surgery, Clinical Hospital “Sveti Duh”, 10000 Zagreb, Croatia
| | - Dinko Vidović
- St. Catherine Specialty Hospital, 49210 Zabok, Croatia; (V.M.); (V.M.); (R.B.); (Ž.J.); (D.H.); (E.R.); (F.Č.); (T.V.); (D.V.); (B.D.); (T.P.); (D.A.); (I.B.)
- St. Catherine Specialty Hospital, 10000 Zagreb, Croatia
- University Hospital “Sisters of Mercy”, Clinic for Traumatology, Draškovićeva 19, 10000 Zagreb, Croatia;
| | | | - Srećko Sabalić
- University Hospital “Sisters of Mercy”, Clinic for Traumatology, Draškovićeva 19, 10000 Zagreb, Croatia;
| | - Borut Dobričić
- St. Catherine Specialty Hospital, 49210 Zabok, Croatia; (V.M.); (V.M.); (R.B.); (Ž.J.); (D.H.); (E.R.); (F.Č.); (T.V.); (D.V.); (B.D.); (T.P.); (D.A.); (I.B.)
- St. Catherine Specialty Hospital, 10000 Zagreb, Croatia
- Department of Orthopaedics and Traumatology, University Hospital Dubrava, 10000 Zagreb, Croatia
| | - Tadija Petrović
- St. Catherine Specialty Hospital, 49210 Zabok, Croatia; (V.M.); (V.M.); (R.B.); (Ž.J.); (D.H.); (E.R.); (F.Č.); (T.V.); (D.V.); (B.D.); (T.P.); (D.A.); (I.B.)
- St. Catherine Specialty Hospital, 10000 Zagreb, Croatia
- Department of Health Studies, University of Split, 21000 Split, Croatia
| | - Darko Antičević
- St. Catherine Specialty Hospital, 49210 Zabok, Croatia; (V.M.); (V.M.); (R.B.); (Ž.J.); (D.H.); (E.R.); (F.Č.); (T.V.); (D.V.); (B.D.); (T.P.); (D.A.); (I.B.)
- St. Catherine Specialty Hospital, 10000 Zagreb, Croatia
- Faculty of Dental Medicine and Health, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
| | - Igor Borić
- St. Catherine Specialty Hospital, 49210 Zabok, Croatia; (V.M.); (V.M.); (R.B.); (Ž.J.); (D.H.); (E.R.); (F.Č.); (T.V.); (D.V.); (B.D.); (T.P.); (D.A.); (I.B.)
- St. Catherine Specialty Hospital, 10000 Zagreb, Croatia
- Department of Traumatology, Medical University Merkur Hospital, 10000 Zagreb, Croatia
- Medical School, University of Split, 21000 Split, Croatia;
- Medical School, University of Mostar, 88000 Mostar, Bosnia and Herzegovina
- Medical School, University of Rijeka, 51000 Rijeka, Croatia
| | - Rok Košir
- Molecular Biology Laboratory, BIA Separations CRO, Labena Ltd., 1000 Ljubljana, Slovenia; (R.K.); (U.P.Z.)
| | - Uršula Prosenc Zmrzljak
- Molecular Biology Laboratory, BIA Separations CRO, Labena Ltd., 1000 Ljubljana, Slovenia; (R.K.); (U.P.Z.)
| | - Dragan Primorac
- St. Catherine Specialty Hospital, 49210 Zabok, Croatia; (V.M.); (V.M.); (R.B.); (Ž.J.); (D.H.); (E.R.); (F.Č.); (T.V.); (D.V.); (B.D.); (T.P.); (D.A.); (I.B.)
- St. Catherine Specialty Hospital, 10000 Zagreb, Croatia
- Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
- Medical School, University of Split, 21000 Split, Croatia;
- Faculty of Dental Medicine and Health, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
- Medical School, University of Mostar, 88000 Mostar, Bosnia and Herzegovina
- Medical School, University of Rijeka, 51000 Rijeka, Croatia
- Medical School REGIOMED, 96450 Coburg, Germany
- Eberly College of Science, State College, The Pennsylvania State University, University Park, PA 16802, USA
- The Henry C. Lee College of Criminal Justice and Forensic Sciences, University of New Haven, West Haven, CT 06516, USA
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32
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Khalil M, Wang D, Hashemi E, Terhune SS, Malarkannan S. Implications of a 'Third Signal' in NK Cells. Cells 2021; 10:cells10081955. [PMID: 34440725 PMCID: PMC8393955 DOI: 10.3390/cells10081955] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 07/26/2021] [Accepted: 07/27/2021] [Indexed: 12/17/2022] Open
Abstract
Innate and adaptive immune systems are evolutionarily divergent. Primary signaling in T and B cells depends on somatically rearranged clonotypic receptors. In contrast, NK cells use germline-encoded non-clonotypic receptors such as NCRs, NKG2D, and Ly49H. Proliferation and effector functions of T and B cells are dictated by unique peptide epitopes presented on MHC or soluble humoral antigens. However, in NK cells, the primary signals are mediated by self or viral proteins. Secondary signaling mediated by various cytokines is involved in metabolic reprogramming, proliferation, terminal maturation, or memory formation in both innate and adaptive lymphocytes. The family of common gamma (γc) cytokine receptors, including IL-2Rα/β/γ, IL-7Rα/γ, IL-15Rα/β/γ, and IL-21Rα/γ are the prime examples of these secondary signals. A distinct set of cytokine receptors mediate a ‘third’ set of signaling. These include IL-12Rβ1/β2, IL-18Rα/β, IL-23R, IL-27R (WSX-1/gp130), IL-35R (IL-12Rβ2/gp130), and IL-39R (IL-23Rα/gp130) that can prime, activate, and mediate effector functions in lymphocytes. The existence of the ‘third’ signal is known in both innate and adaptive lymphocytes. However, the necessity, context, and functional relevance of this ‘third signal’ in NK cells are elusive. Here, we define the current paradigm of the ‘third’ signal in NK cells and enumerate its clinical implications.
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Affiliation(s)
- Mohamed Khalil
- Laboratory of Molecular Immunology and Immunotherapy, Blood Research Institute, Versiti, Milwaukee, WI 53226, USA; (M.K.); (D.W.); (E.H.)
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Dandan Wang
- Laboratory of Molecular Immunology and Immunotherapy, Blood Research Institute, Versiti, Milwaukee, WI 53226, USA; (M.K.); (D.W.); (E.H.)
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Elaheh Hashemi
- Laboratory of Molecular Immunology and Immunotherapy, Blood Research Institute, Versiti, Milwaukee, WI 53226, USA; (M.K.); (D.W.); (E.H.)
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
| | - Scott S. Terhune
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Correspondence: (S.S.T.); (S.M.)
| | - Subramaniam Malarkannan
- Laboratory of Molecular Immunology and Immunotherapy, Blood Research Institute, Versiti, Milwaukee, WI 53226, USA; (M.K.); (D.W.); (E.H.)
- Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA
- Correspondence: (S.S.T.); (S.M.)
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Abstract
The association between inflammation, infection, and venous thrombosis has long been recognized; yet, only in the last decades have we begun to understand the mechanisms through which the immune and coagulation systems interact and reciprocally regulate one another. These interconnected networks mount an effective response to injury and pathogen invasion, but if unregulated can result in pathological thrombosis and organ damage. Neutrophils, monocytes, and platelets interact with each other and the endothelium in host defense and also play critical roles in the formation of venous thromboembolism. This knowledge has advanced our understanding of both human physiology and pathophysiology, as well as identified mechanisms of anticoagulant resistance and novel therapeutic targets for the prevention and treatment of thrombosis. In this review, we discuss the contributions of inflammation and infection to venous thromboembolism.
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Affiliation(s)
- Meaghan E. Colling
- Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
- Clinical Division of Haematology and Haemostaseology, Department of Medicine I, Medical University of Vienna, Vienna, Austria
| | - Benjamin E. Tourdot
- Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Yogendra Kanthi
- Laboratory of Vascular Thrombosis and Inflammation, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
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A novel anti-human IL-1R7 antibody reduces IL-18-mediated inflammatory signaling. J Biol Chem 2021; 296:100630. [PMID: 33823154 PMCID: PMC8018910 DOI: 10.1016/j.jbc.2021.100630] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 03/29/2021] [Accepted: 04/01/2021] [Indexed: 12/17/2022] Open
Abstract
Unchecked inflammation can result in severe diseases with high mortality, such as macrophage activation syndrome (MAS). MAS and associated cytokine storms have been observed in COVID-19 patients exhibiting systemic hyperinflammation. Interleukin-18 (IL-18), a proinflammatory cytokine belonging to the IL-1 family, is elevated in both MAS and COVID-19 patients, and its level is known to correlate with the severity of COVID-19 symptoms. IL-18 binds its specific receptor IL-1 receptor 5 (IL-1R5, also known as IL-18 receptor alpha chain), leading to the recruitment of the coreceptor, IL-1 receptor 7 (IL-1R7, also known as IL-18 receptor beta chain). This heterotrimeric complex then initiates downstream signaling, resulting in systemic and local inflammation. Here, we developed a novel humanized monoclonal anti-IL-1R7 antibody to specifically block the activity of IL-18 and its inflammatory signaling. We characterized the function of this antibody in human cell lines, in freshly obtained peripheral blood mononuclear cells (PBMCs) and in human whole blood cultures. We found that the anti-IL-1R7 antibody significantly suppressed IL-18-mediated NFκB activation, reduced IL-18-stimulated IFNγ and IL-6 production in human cell lines, and reduced IL-18-induced IFNγ, IL-6, and TNFα production in PBMCs. Moreover, the anti-IL-1R7 antibody significantly inhibited LPS- and Candida albicans–induced IFNγ production in PBMCs, as well as LPS-induced IFNγ production in whole blood cultures. Our data suggest that blocking IL-1R7 could represent a potential therapeutic strategy to specifically modulate IL-18 signaling and may warrant further investigation into its clinical potential for treating IL-18-mediated diseases, including MAS and COVID-19.
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Zhang Y, Kuang W, Li D, Li Y, Feng Y, Lyu X, Huang GB, Lian JQ, Yang XF, Hu C, Xie Y, Xue S, Tan J. Natural Killer-Like B Cells Secreting Interleukin-18 Induces a Proinflammatory Response in Periodontitis. Front Immunol 2021; 12:641562. [PMID: 33679805 PMCID: PMC7930384 DOI: 10.3389/fimmu.2021.641562] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 01/27/2021] [Indexed: 12/23/2022] Open
Abstract
Natural killer-like B (NKB) cells, which are newly identified immune subsets, reveal a critical immunoregulatory property in the eradication of microbial infection via the secretion of interleukin (IL)-18. For the first time, this study investigated the role of NKB cells in secreting IL-18 in the pathogenesis of periodontitis. In this study, NKB cells' percentage and IL-18 concentration in peripheral blood and periodontium in periodontitis patients was measured using flow cytometry and ELISA. The role of IL-18 in regulating periodontal inflammation was examined in a Porphyromonas gingivalis (P. gingivalis)-induced periodontitis murine model. Peripheral and periodontal-infiltrating CD3-CD19+NKp46+ NKB cells, which were the main source of IL-18, were elevated and correlated with attachment loss in periodontitis patients. In vitro IL-18 stimulation promoted proinflammatory cytokine production in periodontal ligament cells. P. gingivalis infection induced elevation of IL-18 receptor in periodontium in a periodontitis murine model. IL-18 neutralization not only suppressed P. gingivalis-induced alveolar bone resorption, but also inhibited recruitment of antigen-non-specific inflammatory cells into the periodontium, probably via dampening expressions of cytokines, chemokines, and matrix metalloproteinases. NKB cells secreting IL-18 appeared to be an important mediator in the inflammatory response following intraoral P. gingivalis infection. These findings might be relevant to the development of immunotherapies for periodontitis.
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Affiliation(s)
- Ye Zhang
- Department of Orthodontics, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, China.,Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China.,Department of Infectious Diseases, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Wei Kuang
- Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Department of Oral and Maxillofacial Surgery, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, China
| | - Danfeng Li
- Department of Orthodontics, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, China.,Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Yu Li
- Department of Infectious Diseases, Shaanxi Provincial People's Hospital, The Affiliated Hospital of Xi'an Medical University, Xi'an, China
| | - Yi Feng
- Department of Orthodontics, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, China.,Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Xinwei Lyu
- Department of Orthodontics, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, China.,Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Gao-Bo Huang
- Department of Hepatobiliary Surgery, Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Jian-Qi Lian
- Department of Infectious Diseases, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Xiao-Fei Yang
- Department of Infectious Diseases, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Cheng Hu
- Department of Orthodontics, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, China.,Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Yajuan Xie
- Department of Orthodontics, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, China.,Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Song Xue
- Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Jiali Tan
- Department of Orthodontics, Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, China.,Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China
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Quader M, Mezzaroma E, Kenning K, Toldo S. Modulation of Interleukin-1 and -18 Mediated Injury in Donation after Circulatory Death Mouse Hearts. J Surg Res 2021; 257:468-476. [PMID: 32896815 PMCID: PMC8687874 DOI: 10.1016/j.jss.2020.08.020] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 07/14/2020] [Accepted: 08/02/2020] [Indexed: 01/15/2023]
Abstract
BACKGROUND Donation after circulatory death donors (DCD) can expand the donor pool for heart transplantation, which primarily depends on brain death donors. Ischemia and reperfusion injury are inherent to the DCD process. We hypothesize that pharmacologic inhibition of interleukin-1 (IL-1) and/or IL-18 is protective to DCD hearts. MATERIALS AND METHODS Following clinical protocol, in-situ ischemia time in control beating-heart donor (CBD) and DCD groups was less than 5 and 40 min, respectively. Wild type (WT) C57Bl6/j, IL-1 receptor type I knockout (IL-1RI-KO), and IL-18 KO mice were used. Hearts were reanimated for 90 min on a Langendorff system with Krebs-Henseleit buffer at 37°C, to assess physiologic parameters. Recombinant IL-1 receptor antagonist (IL-1Ra) and/or IL-18 binding protein (IL-18BP) were added to the Krebs-Henseleit buffer to inhibit IL-1 and/or the IL-18 signaling, respectively. RESULTS Developed pressure and ± dP/dt were significantly impaired in the DCD-WT group compared to CBD-WT (P ≤ 0.05). Troponin release was higher in DCD-WT groups. Functional parameters were preserved, and troponin release was significantly less in the DCD knockout groups. Heart function was improved in DCD groups treated with IL-1Ra or IL-18BP compared to the DCD-WT group. CONCLUSIONS Heart function was significantly impaired in the DCD-WT group compared to CBD-WT. Genetic deletion or pharmacologic blockade of IL-1 or IL-18 was protective to DCD hearts.
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Affiliation(s)
- Mohammed Quader
- Cardiovascular Surgery, Virginia Commonwealth University, Richmond, Virginia; Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia.
| | - Eleonora Mezzaroma
- Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia; School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia
| | - Kristine Kenning
- Cardiovascular Surgery, Virginia Commonwealth University, Richmond, Virginia
| | - Stefano Toldo
- Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia; Division of Cardiology, Virginia Commonwealth University, Richmond, Virginia
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Abstract
The human body has a perfect thermoregulatory system to meet the needs of normal life activities. The central regulation of body temperature is mainly explained by the theory of "setting point (setpoint, SP)". Fever is a positive but nonspecific response of the body to infections and other pyrogens, which causes immune cells to release cytokines, leading to a brain protein-mediated rise in body temperature. Cytokines can be roughly divided into 2 categories: proinflammatory cytokines and anti-inflammatory cytokines. IL-1, TNF-α, and IL-6 are proinflammatory cytokines, whereas IL-4 and IL-10 are anti-inflammatory cytokines. IL-2 is a cytokine that can both activate and inhibit immunity. IL-8 is a neutrophil chemotactic factor, and IFN is a cytokine that plays a key role in the proper induction and maintenance of innate and acquired immunity. This article reviews the pathophysiological characteristics of fever and the cytokines related to fever (IL-2, 4, 6, 8, 10, IFN, TNF, etc.).
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Affiliation(s)
- Jinfeng Lai
- Department of Infectious Diseases, First Affiliated Hospital of Soochow University, Suzhou, China
| | - Huichun Wu
- Department of Infectious Diseases, First Affiliated Hospital of Soochow University, Suzhou, China
| | - Ailan Qin
- Department of Infectious Diseases, First Affiliated Hospital of Soochow University, Suzhou, China
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Ali MA, Abu Damir H, Ali OM, Amir N, Tariq S, Greenwood MP, Lin P, Gillard B, Murphy D, Adem A. The effect of long-term dehydration and subsequent rehydration on markers of inflammation, oxidative stress and apoptosis in the camel kidney. BMC Vet Res 2020; 16:458. [PMID: 33228660 PMCID: PMC7686779 DOI: 10.1186/s12917-020-02628-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Accepted: 10/19/2020] [Indexed: 12/24/2022] Open
Abstract
Background Dehydration has deleterious effects in many species, but camels tolerate long periods of water deprivation without serious health compromise. The kidney plays crucial role in water conservation, however, some reports point to elevated kidney function tests in dehydrated camels. In this work, we investigated the effects of dehydration and rehydration on kidney cortex and medulla with respect to pro-inflammatory markers, oxidative stress and apoptosis along with corresponding gene expression. Results The cytokines IL-1β and IL-18 levels were significantly elevated in the kidney cortex of dehydrated camel, possibly expressed by tubular epithelium, podocytes and/or mesangial cells. Elevation of IL-18 persisted after rehydration. Dehydration induced oxidative stress in kidney cortex evident by significant increases in MDA and GSH, but significant decreases in SOD and CAT. In the medulla, CAT decreased significantly, but MDA, GSH and SOD levels were not affected. Rehydration abolished the oxidative stress. In parallel with the increased levels of MDA, we observed increased levels of PTGS1 mRNA, in MDA synthesis pathway. GCLC mRNA expression level, involved in GSH synthesis, was upregulated in kidney cortex by rehydration. However, both SOD1 and SOD3 mRNA levels dropped, in parallel with SOD activity, in the cortex by dehydration. There were significant increases in caspases 3 and 9, p53 and PARP1, indicating apoptosis was triggered by intrinsic pathway. Expression of BCL2l1 mRNA levels, encoding for BCL-xL, was down regulated by dehydration in cortex. CASP3 expression level increased significantly in medulla by dehydration and continued after rehydration whereas TP53 expression increased in cortex by rehydration. Changes in caspase 8 and TNF-α were negligible to instigate extrinsic apoptotic trail. Generally, apoptotic markers were extremely variable after rehydration indicating that animals did not fully recover within three days. Conclusions Dehydration causes oxidative stress in kidney cortex and apoptosis in cortex and medulla. Kidney cortex and medulla were not homogeneous in all parameters investigated indicating different response to dehydration/rehydration. Some changes in tested parameters directly correlate with alteration in steady-state mRNA levels.
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Affiliation(s)
- Mahmoud A Ali
- Department of Pharmacology, CollegeofMedicine&HealthSciences, United Arab Emirates University, Al- Ain, United Arab Emirates
| | - Hassan Abu Damir
- Department of Pharmacology, CollegeofMedicine&HealthSciences, United Arab Emirates University, Al- Ain, United Arab Emirates
| | - Osman M Ali
- College of Medicine and Public Health, Flinders University, Adelaide, Australia
| | - Naheed Amir
- Department of Pharmacology, CollegeofMedicine&HealthSciences, United Arab Emirates University, Al- Ain, United Arab Emirates
| | - Saeed Tariq
- Department of Anatomy, CollegeofMedicine&HealthSciences, Emirates University, Al-Ain, United Arab Emirates
| | - Michael P Greenwood
- Molecular Neuroendocrinology Research Group, Bristol Medical School, Translational Health Sciences, University of Bristol, Dorothy Hodgkin Building, Bristol, BS13NY, UK
| | - Panjiao Lin
- Molecular Neuroendocrinology Research Group, Bristol Medical School, Translational Health Sciences, University of Bristol, Dorothy Hodgkin Building, Bristol, BS13NY, UK
| | - Benjamin Gillard
- Molecular Neuroendocrinology Research Group, Bristol Medical School, Translational Health Sciences, University of Bristol, Dorothy Hodgkin Building, Bristol, BS13NY, UK
| | - David Murphy
- Molecular Neuroendocrinology Research Group, Bristol Medical School, Translational Health Sciences, University of Bristol, Dorothy Hodgkin Building, Bristol, BS13NY, UK.
| | - Abdu Adem
- Department of Pharmacology, CollegeofMedicine&HealthSciences, United Arab Emirates University, Al- Ain, United Arab Emirates. .,Department of Pharmacology, College of Medicine and Health Sciences, Khalifa University, P.O.Box 127788, Abu Dhabi, UAE.
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Abstract
Tumors represent a hostile environment for the effector cells of cancer immunosurveillance. Immunosuppressive receptors and soluble or membrane-bound ligands are abundantly exposed and released by malignant entities and their stromal accomplices. As a consequence, executioners of antitumor immunity inefficiently navigate across cancer tissues and fail to eliminate malignant targets. By inducing immunogenic cancer cell death, oncolytic viruses profoundly reshape the tumor microenvironment. They trigger the local spread of danger signals and tumor-associated (as well as viral) antigens, thus attracting antigen-presenting cells, promoting the activation and expansion of lymphocytic populations, facilitating their infiltration in the tumor bed, and reinvigorating cytotoxic immune activity. The present review recapitulates key chemokines, growth factors and other cytokines that orchestrate this ballet of antitumoral leukocytes upon oncolytic virotherapy.
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Affiliation(s)
- Jonathan G Pol
- Centre de Recherche des Cordeliers, Equipe 11 labellisée par la Ligue Nationale contre le Cancer, INSERM, Sorbonne Université, Université de Paris, Paris, France; Gustave Roussy Cancer Campus, Metabolomics and Cell Biology Platforms, Villejuif, France.
| | - Samuel T Workenhe
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada
| | - Prathyusha Konda
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada
| | - Shashi Gujar
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada; Department of Pathology, Dalhousie University, Halifax, NS, Canada; Department of Biology, Dalhousie University, Halifax, NS, Canada; Beatrice Hunter Cancer Research Institute, Halifax, NS, Canada
| | - Guido Kroemer
- Centre de Recherche des Cordeliers, Equipe 11 labellisée par la Ligue Nationale contre le Cancer, INSERM, Sorbonne Université, Université de Paris, Paris, France; Gustave Roussy Cancer Campus, Metabolomics and Cell Biology Platforms, Villejuif, France; Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France; Suzhou Institute for Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, China; Karolinska Institute, Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden.
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Nlrp3 Inflammasome Inhibitor MCC950 Ameliorates Obliterative Bronchiolitis by Inhibiting Th1/Th17 Response and Promoting Treg Response After Orthotopic Tracheal Transplantation in Mice. Transplantation 2020; 104:e151-e163. [PMID: 32108749 DOI: 10.1097/tp.0000000000003208] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Obliterative bronchiolitis (OB) remains the major complication limiting long-term survival of patients after lung transplantation. We aimed to explore the effects of the selective NACHT, LRR, and PYD domains-containing protein 3 (Nlrp3) inflammasome inhibitor MCC950 on the pathogenesis of OB. METHODS Mouse orthotopic tracheal transplants were performed to mimic OB. MCC950 (50 mg/kg) or saline was intraperitoneally injected daily. The luminal occlusion rate and collagen deposition were evaluated by hematoxylin and eosin and Masson's trichrome staining, respectively. Infiltration of CD4+, CD8+ T cells, and neutrophils was detected with immunohistochemical staining. The frequencies of T helper 1 cell (Th1), T helper 17 cell (Th17), and regulatory T cells (Treg) were measured by flow cytometry. Cytokine levels were measured by ELISA kits. RESULTS MCC950 treatment significantly inhibited Nlrp3 inflammasome activation after allogeneic tracheal transplant and markedly decreased the luminal occlusion rate and collagen deposition in the allograft. The numbers of infiltrating CD4+, CD8+ T cells, and neutrophils in the allograft were also significantly reduced by MCC950 treatment. MCC950 dramatically decreased the frequencies of Th1/Th17 cells and the levels of interferon gamma/interleukin (IL)-17A and increased the Treg cell frequencies and IL-10 level; however, these effects were abolished by the addition of IL-1β and IL-18 both in vitro and in vivo. OB was also rescued by the addition of IL-1β and/or IL-18. CONCLUSIONS Blocking Nlrp3 inflammasome activation with MCC950 ameliorates OB lesions. The mechanistic analysis showed that MCC950 regulated the balance of Th1/Th17 and Treg cells and that this process is partially mediated by inhibition of IL-1β and IL-18. Therefore, targeting the Nlrp3 inflammasome is a promising strategy for controlling OB after lung transplantation.
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IMMUNOMEDIATOR GENE TRANSCRIPTION PROFILING IN BELUGA WHALE ( DELPHINAPTERUS LEUCAS) CLINICAL CASES. J Zoo Wildl Med 2020; 51:334-349. [PMID: 32549563 DOI: 10.1638/2018-0225] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/02/2019] [Indexed: 11/21/2022] Open
Abstract
There is an unmet need for specific diagnostics of immune perturbations and inflammation in beluga whale (Delphinapterus leucas) clinical care. Quantitative real-time polymerase chain reaction (qPCR) has been used to measure immunomediator gene transcription in beluga whales. The study hypothesis was that a qPCR-based immunomediator assay would supplement routine clinical data with specific and sensitive information on immune status. Two beluga whale clinical cases provided an opportunity to test this hypothesis: a whale with a skin laceration and a whale with gastrointestinal inflammation. Mitogen-stimulated immunomediator gene transcription (MSIGT) was compared between the cases and healthy contact whales. In both case studies, mitogens increased transcription of IL1B, PTGS2 (Cox-2), TNF, HIF1A, and IL2 but decreased IL10 transcription in peripheral blood mononuclear cells (PBMC) from the abnormal whale over the control. Correlations were identified between most immunomediators tested and one or more standard blood clinical values. Considering all 15 immunomediators tested, the whale with gastrointestinal inflammation had a more unique MSIGT signature than the whale with a laceration. These results support further elucidation of beluga whale PBMC cytokine profiles for use as immune biomarkers.
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Ravimohan S, Maenetje P, Auld SC, Ncube I, Mlotshwa M, Chase W, Tiemessen CT, Vangu MDT, Wallis RS, Churchyard G, Weissman D, Kornfeld H, Bisson GP. A Common NLRC4 Gene Variant Associates With Inflammation and Pulmonary Function in Human Immunodeficiency Virus and Tuberculosis. Clin Infect Dis 2020; 71:924-932. [PMID: 31751447 PMCID: PMC7428399 DOI: 10.1093/cid/ciz898] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Accepted: 09/27/2019] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Inflammasomes mediate inflammation in adults living with both human immunodeficiency virus (HIV) and tuberculosis (TB), but the relevance of inflammasome gene polymorphisms in TB-associated pulmonary damage is unknown. We hypothesized that functional single-nucleotide polymorphisms (SNPs) in inflammasome pathway genes modify systemic and pulmonary inflammation, contributing to respiratory impairment in adults living with HIV/pulmonary TB. METHODS This was a prospective cohort study set in South Africa following individuals living with HIV/TB up to 48 weeks post-antiretroviral therapy (ART) initiation. Ten functional SNPs in 5 inflammasome pathway genes were related to circulating inflammatory biomarkers and lung function assessed by spirometry pre- and post-ART initiation. Analyses used 2-sided t tests, Wilcoxon rank sum tests, Spearman correlation coefficients, linear regression, and generalized estimating equation models. RESULTS Among 102 patients with baseline samples, the minor allele (T) in NLRC4 rs385076 was independently associated with lower levels of interleukin (IL)-18 and IL-6 before and up to 12 weeks post-ART initiation (Benjamini-Hochberg corrected P values < .02). Patients with the CT/TT genotypes also had improved lung function vs CC patients up to 48 weeks post-ART initiation (forced vital capacity, 206 mL higher; 95% confidence interval [CI], 67-345 mL; P = .004 and forced expiratory volume in 1 second, 143 mL higher; 95% CI, 11-274 mL; P = .034). CONCLUSIONS A common SNP in the NLRC4 inflammasome may modify TB-associated inflammation in clinically relevant ways. This SNP may identify high-risk groups for lung damage in TB. Inhibition of NLRC4 activity may be an important approach for TB host-directed therapy.
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Affiliation(s)
- Shruthi Ravimohan
- Department of Medicine, Division of Infectious Diseases, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | | | - Sara C Auld
- Department of Medicine, Emory University Rollins School of Public Health and School of Medicine, Atlanta, Georgia, USA, Johannesburg, South Africa
| | - Itai Ncube
- The Aurum Institute, Johannesburg, South Africa
| | | | - William Chase
- Department of Medicine, Division of Infectious Diseases, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Caroline T Tiemessen
- Centre for HIV-1 and STIs, National Institute for Communicable Diseases, and Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Mboyo-Di-Tamba Vangu
- Nuclear Medicine, CM Johannesburg Academic Hospital, University of the Witwatersrand, Johannesburg, South Africa
| | | | - Gavin Churchyard
- The Aurum Institute, Johannesburg, South Africa
- School of Public Health, University of the Witwatersrand, Johannesburg, South Africa
| | - Drew Weissman
- Department of Medicine, Division of Infectious Diseases, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Hardy Kornfeld
- Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Gregory P Bisson
- Department of Medicine, Division of Infectious Diseases, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Department of Biostatistics, Epidemiology, and Informatics, Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
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Abstract
A limited number of peripheral targets generate pain. Inflammatory mediators can sensitize these. The review addresses targets acting exclusively or predominantly on sensory neurons, mediators involved in inflammation targeting sensory neurons, and mediators involved in a more general inflammatory process, of which an analgesic effect secondary to an anti-inflammatory effect can be expected. Different approaches to address these systems are discussed, including scavenging proinflammatory mediators, applying anti-inflammatory mediators, and inhibiting proinflammatory or facilitating anti-inflammatory receptors. New approaches are contrasted to established ones; the current stage of progress is mentioned, in particular considering whether there is data from a molecular and cellular level, from animals, or from human trials, including an early stage after a market release. An overview of publication activity is presented, considering a IuPhar/BPS-curated list of targets with restriction to pain-related publications, which was also used to identify topics.
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Affiliation(s)
- Cosmin I Ciotu
- Center of Physiology and Pharmacology, Medical University of Vienna, Schwarzspanierstrasse 17, 1090, Vienna, Austria
| | - Michael J M Fischer
- Center of Physiology and Pharmacology, Medical University of Vienna, Schwarzspanierstrasse 17, 1090, Vienna, Austria.
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44
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Abstract
PURPOSE OF REVIEW IL-18 is a pleiotropic cytokine involved in the regulation of innate and adaptive immune responses. IL-18 pro-inflammatory activities are finely regulated in vivo by the inhibitory effects of the soluble IL-18-binding protein (IL-18BP). The elevation of circulating levels of IL-18 has been described in children with systemic juvenile idiopathic arthritis (sJIA). In the recent years, the role of IL-18 in the pathogenesis of secondary haemophagocytic lymphohistiocytosis (sHLH), also referred to as macrophage activation syndrome (MAS), in the context of autoinflammatory diseases, including sJIA, is emerging. RECENT FINDINGS A large number of studies in patients and animal models pointed to the imbalance in IL-18/IL-18BP levels, causing increased systemic levels of free bioactive IL-18, as a predisposing factor in the development of MAS. Although the exact mechanisms involved in the development of MAS are not clearly understood, increasing evidence demonstrate the role of IL-18 in upregulating the production of interferon (IFN)-γ. SUMMARY On the basis of the first emerging data on the possibility of blocking IL-18, we here discuss the scientific rationale for neutralizing the IL-18/IFNγ axis in the prevention and treatment of sHLH and MAS.
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45
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Emerging Roles for Interleukin-18 in the Gastrointestinal Tumor Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1240:59-72. [PMID: 32060888 DOI: 10.1007/978-3-030-38315-2_5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Interleukin (IL)-18, a member of the IL-1 family of cytokines, has emerged as a key regulator of mucosal homeostasis within the gastrointestinal tract. Like other members of this family, IL-18 is secreted as an inactive protein and is processed into its active form by caspase-1, although other contributors to precursor processing are emerging.Numerous studies have evaluated the role of IL-18 within the gastrointestinal tract using genetic or complementary pharmacological tools and have revealed multiple roles in tumorigenesis. Most striking among these are the divergent roles for IL-18 in colon and gastric cancers. Here, we review our current understanding of IL-18 biology and how this applies to colorectal and gastric cancers.
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Rex DAB, Agarwal N, Prasad TSK, Kandasamy RK, Subbannayya Y, Pinto SM. A comprehensive pathway map of IL-18-mediated signalling. J Cell Commun Signal 2019; 14:257-266. [PMID: 31863285 DOI: 10.1007/s12079-019-00544-4] [Citation(s) in RCA: 77] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Accepted: 12/06/2019] [Indexed: 02/07/2023] Open
Abstract
Interleukin-18 (IL-18) is a member of the IL-1 family of cytokines and was initially described as an IFN-γ-inducing factor derived from anti-CD3-stimulated T-helper (Th)1 cells. IL-18 plays a significant role in the activation of hematopoietic cell types mediating both Th1 and Th2 responses and is the primary inducer of interferon-γ in these cells. The biological activity of IL-18 is mediated through its binding to the IL-18 receptor complex and activation of nuclear factor-κB (NF-κB), culminating in the production and release of several cytokines, chemokines, and cellular adhesion molecules. In certain cell types, IL-18 also activates mitogen-activated protein kinases (MAPKs) and phosphoinositide 3-kinase/ AKT serine/threonine kinase (PI3K/AKT) signaling modules leading to the production and release of proinflammatory cytokines. IL-18-mediated signaling acts as one of the vital components of the immunomodulatory cytokine networks involved in host defense, inflammation, and tissue regeneration. Albeit its biomedical importance, a comprehensive resource of IL-18 mediated signaling pathway is currently lacking. In this study, we report on the development of an integrated pathway map of IL-18/IL-18R signaling. The pathway map was developed through literature mining from published literature based on manual curation guidelines adapted from NetPath and includes information on 16 protein-protein interaction events, 38 enzyme-catalysis events, 12 protein translocation events, 26 activations/inhibition events, transcriptional regulators, 230 gene regulation events and 84 induced protein expression events. The IL-18 signaling pathway can be freely accessed through the WikiPathways database (https://www.wikipathways.org/index.php/Pathway:WP4754).
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Affiliation(s)
- D A B Rex
- Center for Systems Biology and Molecular Medicine, Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore, India
| | - Nupur Agarwal
- Center for Systems Biology and Molecular Medicine, Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore, India
| | - T S Keshava Prasad
- Center for Systems Biology and Molecular Medicine, Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore, India
| | - Richard K Kandasamy
- Centre of Molecular Inflammation Research (CEMIR), and Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology, N-7491, Trondheim, Norway
| | - Yashwanth Subbannayya
- Center for Systems Biology and Molecular Medicine, Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore, India. .,Centre of Molecular Inflammation Research (CEMIR), and Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology, N-7491, Trondheim, Norway.
| | - Sneha M Pinto
- Center for Systems Biology and Molecular Medicine, Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore, India. .,Centre of Molecular Inflammation Research (CEMIR), and Department of Clinical and Molecular Medicine (IKOM), Norwegian University of Science and Technology, N-7491, Trondheim, Norway.
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47
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Yang F, He Y, Zhai Z, Sun E. Programmed Cell Death Pathways in the Pathogenesis of Systemic Lupus Erythematosus. J Immunol Res 2019; 2019:3638562. [PMID: 31871956 PMCID: PMC6913273 DOI: 10.1155/2019/3638562] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Revised: 08/04/2019] [Accepted: 10/18/2019] [Indexed: 02/07/2023] Open
Abstract
Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease characterized by excessive inflammatory and immune responses and tissue damage. Increasing evidence has demonstrated the important role of programmed cell death in SLE pathogenesis. When apoptosis encounters with defective clearance, accumulated apoptotic cells lead to secondary necrosis. Different forms of lytic cell death, including secondary necrosis after apoptosis, NETosis, necroptosis, and pyroptosis, contribute to the release of damage-associated molecular patterns (DAMPs) and autoantigens, resulting in triggering immunity and tissue damage in SLE. However, the role of autophagy in SLE pathogenesis is in dispute. This review briefly discusses different forms of programmed cell death pathways and lay particular emphasis on inflammatory cell death pathways such as NETosis, pyroptosis, and necroptosis and their roles in the inflammatory and immune responses in SLE.
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Affiliation(s)
- Fangyuan Yang
- Department of Rheumatology and Immunology, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China
- Institute of Clinical Immunology, Academy of Orthopedics, Guangdong Province, Guangzhou, China
| | - Yi He
- Department of Rheumatology and Immunology, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China
- Institute of Clinical Immunology, Academy of Orthopedics, Guangdong Province, Guangzhou, China
| | - Zeqing Zhai
- Department of Rheumatology and Immunology, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China
- Institute of Clinical Immunology, Academy of Orthopedics, Guangdong Province, Guangzhou, China
| | - Erwei Sun
- Department of Rheumatology and Immunology, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China
- Institute of Clinical Immunology, Academy of Orthopedics, Guangdong Province, Guangzhou, China
- Department of Rheumatology and Immunology, Shunde Hospital, Southern Medical University, Guangzhou, China
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48
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Liu F, Endo Y, Romantseva T, Wu WW, Akue A, Shen RF, Golding H, Zaitseva M. T cell-derived soluble glycoprotein GPIbα mediates PGE 2 production in human monocytes activated with the vaccine adjuvant MDP. Sci Signal 2019; 12:12/602/eaat6023. [PMID: 31594856 DOI: 10.1126/scisignal.aat6023] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Vaccine adjuvants containing analogs of microbial products activate pattern recognition receptors (PRRs) on antigen-presenting cells, including monocytes and macrophages, which can cause prostaglandin E2 (PGE2) release and consequently undesired inflammatory responses and fever in vaccine recipients. Here, we studied the mechanism of PGE2 production by human monocytes activated with muramyl dipeptide (MDP) adjuvant, which activates cytosolic nucleotide-binding oligomerization domain 2 (NOD2). In rabbits, administration of MDP elicited an early increase in PGE2 followed by fever. In human monocytes, MDP alone did not induce PGE2 production. However, high amounts of PGE2 and the proinflammatory cytokines IL-1β and IL-6 were secreted by monocytes activated with MDP in the presence of conditioned medium obtained from CD3 bead-isolated T cells (Tc CM) but not from those isolated without CD3 beads. Mass spectrometry and immunoblotting revealed that the costimulatory factor in Tc CM was glycoprotein Ib α (GPIbα). Antibody-mediated blockade of GPIbα or of its receptor, Mac-1 integrin, inhibited the secretion of PGE2, IL-1β, and IL-6 in MDP + Tc CM-activated monocytes, whereas recombinant GPIbα protein increased PGE2 production by MDP-treated monocytes. In vivo, COX2 mRNA abundance was reduced in the liver and spleen of Mac-1 KO mice after administration of MDP compared with that of treated wild-type mice. Our findings suggest that the production of PGE2 and proinflammatory cytokines by MDP-activated monocytes is mediated by cooperation between two signaling pathways: one delivered by MDP through NOD2 and a second through activation of Mac-1 by T cell-derived GPIbα.
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Affiliation(s)
- Fengjie Liu
- Division of Viral Products, Food and Drug Administration, Silver Spring, MD 20993, USA
| | - Yukinori Endo
- Division of Viral Products, Food and Drug Administration, Silver Spring, MD 20993, USA
| | - Tatiana Romantseva
- Division of Viral Products, Food and Drug Administration, Silver Spring, MD 20993, USA
| | - Wells W Wu
- Facility for Biotechnology Resources, Food and Drug Administration, Silver Spring, MD 20993, USA
| | - Adovi Akue
- Flow Cytometry Core, Center for Biologics Evaluation and Research (CBER), Food and Drug Administration, Silver Spring, MD 20993, USA
| | - Rong-Fong Shen
- Facility for Biotechnology Resources, Food and Drug Administration, Silver Spring, MD 20993, USA
| | - Hana Golding
- Division of Viral Products, Food and Drug Administration, Silver Spring, MD 20993, USA
| | - Marina Zaitseva
- Division of Viral Products, Food and Drug Administration, Silver Spring, MD 20993, USA.
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49
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The IL-1 family of cytokines and receptors in rheumatic diseases. Nat Rev Rheumatol 2019; 15:612-632. [DOI: 10.1038/s41584-019-0277-8] [Citation(s) in RCA: 246] [Impact Index Per Article: 41.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/18/2019] [Indexed: 02/07/2023]
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50
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Kaneko N, Kurata M, Yamamoto T, Morikawa S, Masumoto J. The role of interleukin-1 in general pathology. Inflamm Regen 2019; 39:12. [PMID: 31182982 PMCID: PMC6551897 DOI: 10.1186/s41232-019-0101-5] [Citation(s) in RCA: 382] [Impact Index Per Article: 63.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2019] [Accepted: 05/07/2019] [Indexed: 12/19/2022] Open
Abstract
Interleukin-1, an inflammatory cytokine, is considered to have diverse physiological functions and pathological significances and play an important role in health and disease. In this decade, interleukin-1 family members have been expanding and evidence is accumulating that highlights the importance of interleukin-1 in linking innate immunity with a broad spectrum of diseases beyond inflammatory diseases. In this review, we look back on the definition of "inflammation" in traditional general pathology and discuss new insights into interleukin-1 in view of its history and the molecular bases of diseases, as well as current progress in therapeutics.
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Affiliation(s)
- Naoe Kaneko
- Department of Pathology, Ehime University Graduate School of Medicine and Proteo-Science Center, Shitsukawa 454, Toon, Ehime 791-0295 Japan
| | - Mie Kurata
- Department of Pathology, Ehime University Graduate School of Medicine and Proteo-Science Center, Shitsukawa 454, Toon, Ehime 791-0295 Japan
| | - Toshihiro Yamamoto
- Department of Pathology, Ehime University Graduate School of Medicine and Proteo-Science Center, Shitsukawa 454, Toon, Ehime 791-0295 Japan
| | - Shinnosuke Morikawa
- Department of Pathology, Ehime University Graduate School of Medicine and Proteo-Science Center, Shitsukawa 454, Toon, Ehime 791-0295 Japan
| | - Junya Masumoto
- Department of Pathology, Ehime University Graduate School of Medicine and Proteo-Science Center, Shitsukawa 454, Toon, Ehime 791-0295 Japan
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