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Tao H, Wang C, Zou C, Zhu H, Zhang W. Unraveling the potential of neuroinflammation and autophagy in schizophrenia. Eur J Pharmacol 2025; 997:177469. [PMID: 40054715 DOI: 10.1016/j.ejphar.2025.177469] [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: 10/22/2024] [Revised: 02/03/2025] [Accepted: 03/04/2025] [Indexed: 03/17/2025]
Abstract
Schizophrenia (SCZ) is a complex and chronic psychiatric disorder that affects a significant proportion of the global population. Although the precise etiology of SCZ remains uncertain, recent studies have underscored the involvement of neuroinflammation and autophagy in its pathogenesis. Neuroinflammation, characterized by hyperactivated microglia and markedly elevated pro-inflammatory cytokines, has been observed in postmortem brain tissues of SCZ patients and is closely associated with disease severity. Autophagy, a cellular process responsible for eliminating damaged components and maintaining cellular homeostasis, is believed to play a pivotal role in neuronal health and the onset of SCZ. This review explores the roles and underlying mechanisms of neuroinflammation and autophagy in SCZ, with a particular focus on their intricate interplay. Additionally, we provide an overview of potential therapeutic strategies aimed at modulating neuroinflammation and autophagy, including nutritional interventions, anti-inflammatory drugs, antipsychotics, and plant-derived natural compounds. The review also addresses the dual effects of antipsychotics on autophagy. Our objective is to translate these insights into clinical practice, expanding the therapeutic options available to improve the overall health and well-being of individuals with SCZ.
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Affiliation(s)
- Hongxia Tao
- Mental Health Center, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Congyin Wang
- Department of Emergency Medicine, Chengdu Fifth People's Hospital, Chengdu, Sichuan, 611130, China
| | - Chuan Zou
- Department of General Practice, Chengdu Fifth People's Hospital, Chengdu, Sichuan, 611130, China
| | - Hongru Zhu
- Mental Health Center, West China Hospital, Sichuan University, Chengdu, 610041, China.
| | - Wei Zhang
- Mental Health Center, West China Hospital, Sichuan University, Chengdu, 610041, China.
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2
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Seaton-Terry A, Hunter Z, Lewis M, Fisher S, Bray E, Townsend B, Gabure S, Daniel L, Whalen M. Toll-Like Receptors in Pentachlorophenol- and Dibutyltin-Induced Production of Pro-Inflammatory Cytokines, Interleukin (IL)-1β, and IL-6, by Human Immune Cells. J Appl Toxicol 2025; 45:976-993. [PMID: 39914831 PMCID: PMC12064381 DOI: 10.1002/jat.4762] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 01/13/2025] [Accepted: 01/27/2025] [Indexed: 05/11/2025]
Abstract
Pentachlorophenol (PCP) and dibutyltin dichloride (DBT) contaminate the environment due to their diverse applications. PCP has been found from 0.26 to 5 μM in the serum of exposed individuals and at an average of 0.15 μM in the unexposed. DBT has been detected in human blood at levels up to 0.3 μM. Exposure to these contaminants is linked to pathological conditions including cancer. Interleukin-1 beta (IL-1β) and IL-6 are pro-inflammatory cytokines that when produced inappropriately can cause chronic inflammation, which is linked to pathologies including autoimmune diseases and cancer. PCP and DBT have been shown to increase the production of IL-1β and IL-6 by immune cells in a MAP kinase (MAPK) dependent process. Toll-like receptors (TLRs) activate the signaling pathways linked to MAPK that lead to production of these cytokines. This study demonstrates that PCP-induced production of IL-1β and IL-6 is dependent on TLR4 and TLR8, and independent of TLR1/2, TLR2, and TLR3. Additionally, DBT-induced IL-6 production depends on TLR1/2, whereas IL-1β production does not. Blocking the TLR-linked adapter protein, MyD88, lead to a loss of both PCP and DBT stimulation of IL-1β and IL-6. These findings indicate that both PCP and DBT interact with selected TLRs as part of their mechanisms of elevating the levels of critical pro-inflammatory cytokines, which may contribute to chronic inflammation and its related pathologies.
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Affiliation(s)
| | - Zinia Hunter
- Department of Biology, Tennessee State University, Nashville, Tennessee, USA
| | - Meaghan Lewis
- Department of Biology, Tennessee State University, Nashville, Tennessee, USA
| | - Sophia Fisher
- Department of Biology, Tennessee State University, Nashville, Tennessee, USA
| | - Ellie Bray
- Department of Biology, Tennessee State University, Nashville, Tennessee, USA
| | - Brian Townsend
- Department of Biology, Tennessee State University, Nashville, Tennessee, USA
| | - Saleban Gabure
- Deapartment of Chemistry, Tennessee State University, Nashville, Tennessee, USA
| | - Latoya Daniel
- Department of Biology, Tennessee State University, Nashville, Tennessee, USA
| | - Margaret Whalen
- Deapartment of Chemistry, Tennessee State University, Nashville, Tennessee, USA
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3
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Wu Q, Wang Q, Hu K, Luo T, Liu J, Xue Y, Li L, Yang C, Lin R, Pan H, Wang J, Guo Z. Proline/serine-rich coiled-coil protein 1 alleviates pyroptosis in murine bone marrow-derived macrophages. Acta Biochim Biophys Sin (Shanghai) 2025. [PMID: 39935324 DOI: 10.3724/abbs.2025012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/13/2025] Open
Abstract
Pyroptosis is a regulated inflammatory cell death process that plays an essential role in various diseases. This study investigates the role of proline/serine-rich coiled-coil protein 1 (PSRC1) in pyroptosis and inflammation in macrophages. This study reports that PSRC1 expression is decreased in pyroptotic macrophages and that knockout of PSRC1 exacerbates pyroptosis and inflammation. PSRC1 overexpression alleviates pyroptosis and inflammation in macrophages. RNA-seq analysis reveals that PSRC1 regulates the expression of genes involved in the extracellular matrix (ECM). Specifically, PSRC1 downregulates the expression of periostin (POSTN), an ECM component. Knockdown of POSTN suppresses macrophage pyroptosis mediated by low expression of PSRC1. These findings suggest that PSRC1 can alleviate pyroptosis and inflammation in bone marrow-derived macrophages (BMDMs) by regulating the ECM and negatively regulating POSTN. This study provides insights into the role of PSRC1 in macrophage pyroptosis and identifies a potential target for the treatment of inflammatory diseases. Further research is needed to confirm these findings in vivo and in various disease models.
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Affiliation(s)
- Qiao Wu
- Department of Cardiology, Huiqiao Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou 510080, China
| | - Qianqian Wang
- Department of Cardiology, Huiqiao Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou 510080, China
| | - Kexin Hu
- Department of Cardiology, Huiqiao Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou 510080, China
| | - Tiantian Luo
- Department of Cardiology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China; Chengdu 610014, China
| | - Jichen Liu
- Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou 510080, China
| | - Yazhi Xue
- Department of General Practice, Nanfang Hospital, Southern Medical University, Guangzhou 510080, China
| | - Ling Li
- Department of Cardiology, Huiqiao Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou 510080, China
| | - Cuiqi Yang
- Department of Cardiology, Huiqiao Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou 510080, China
| | - Rongzhan Lin
- Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou 510080, China
| | - Hangyu Pan
- Department of Cardiology, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou 510080, China
| | - Jinhao Wang
- Department of Cardiology, Huiqiao Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou 510080, China
| | - Zhigang Guo
- Department of Cardiology, Huiqiao Medical Center, Nanfang Hospital, Southern Medical University, Guangzhou 510080, China
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Falconer-Turner A, Brooks K, Ogaga E, Whalen MM. Flame retardant, hexabromocyclododecane, increases production of pro-inflammatory cytokines, interleukin 1-beta and interleukin 6, in human immune cells. J Appl Toxicol 2025; 45:273-287. [PMID: 39285786 PMCID: PMC11748055 DOI: 10.1002/jat.4700] [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: 07/18/2024] [Revised: 08/22/2024] [Accepted: 09/03/2024] [Indexed: 01/19/2025]
Abstract
Hexabromocyclododecane (HBCD) is an environmental contaminant due to its use as a flame retardant in a variety of applications ranging from building insulation, furniture upholstery, and housing for appliances and electronics. HBCD is found in wildlife, human breastmilk, and serum. Interleukin 1-beta (IL-1β) and interleukin 6 (IL-6) are pro-inflammatory cytokines, whose dysregulation is associated with chronic inflammation and the pathologies that result, such as tumor growth, rheumatoid arthritis, Crohn's disease, and multiple sclerosis. HBCD has been shown to increase the secretion of both IL-1β and IL-6 from human immune cells. However, it is not clear if these increases are due solely to HBCD effects on the secretory process or whether it is stimulating cellular production of IL-1β and IL-6. This study examines if HBCD can increase the production of IL-1β and IL-6 by immune cells by simultaneously assessing secreted levels and cellular levels of these cytokines. Additionally, the mechanisms for any observed changes in production are investigated. Peripheral blood mononuclear cells were exposed to HBCD over a range of concentrations and lengths of exposure. HBCD was found to stimulate IL-1β and IL-6 production after 6 hrs. of exposure and production was sustained and intensified at 24 hrs. This increase in IL-1β and IL-6 production appears to, in part, be a result of increased mRNA expression. Additionally, the MAPK pathways, specifically the p38 and p44/42 pathways, appear to be required for HBCD-induced increases in IL-1β and IL-6 production.
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Affiliation(s)
| | - Kameron Brooks
- Department of Chemistry, Tennessee State University,
Nashville, TN 37209
| | - Eseoghene Ogaga
- Department of Biological Sciences, Tennessee State
University, Nashville, TN 37209
| | - Margaret M. Whalen
- Department of Chemistry, Tennessee State University,
Nashville, TN 37209
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Verçosa BLA, Muniz-Junqueira MI, Mineiro ALBB, Melo MN, Vasconcelos AC. Enhanced apoptosis and inflammation allied with autophagic and apoptotic Leishmania amastigotes in the seemingly undamaged ear skin of clinically affected dogs with canine visceral Leishmaniasis. Cell Immunol 2025; 408:104909. [PMID: 39701006 DOI: 10.1016/j.cellimm.2024.104909] [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: 09/16/2024] [Revised: 11/30/2024] [Accepted: 12/06/2024] [Indexed: 12/21/2024]
Abstract
Programmed cell death plays a relevant role in the pathogenesis of visceral Leishmaniasis. Apoptosis selects suitable parasites, regulating parasite density, whereas autophagy eliminates pathogens. This study aimed to assess the inflammation and apoptosis in inflammatory cells and presents a unique description of the presence of autophagic and apoptotic Leishmania amastigotes in naturally Leishmania-infected dogs. Fragments from seemingly undamaged ear skin of sixteen Leishmania-infected dogs and seven uninfected dogs were evaluated through histomorphometry, ultrastructural, immunohistochemical and transmission electron microscopy (TEM) analyses. Leishmania amastigotes were present on seemingly undamaged ear skin only in clinically affected dogs. Parasite load, morphometrical parameters of inflammation and apoptotic index of inflammatory cells were higher in clinically affected animals and were related to clinical manifestations. Apoptotic index and morphometric parameters of the inflammatory infiltrate in undamaged ear skin were positively correlated with parasite load. Apoptotic and non-apoptotic Leishmania amastigotes were observed within neutrophils and macrophages. Leishmania amastigotes were positive for Bax, a marker for apoptosis, by immunohistochemistry. Morphological characteristics of apoptosis and autophagy in Leishmania amastigotes were observed only in phagocytes of clinically affected dogs. Positive correlations were found between histomorphometry and clinical manifestations. Our results showed that apoptosis and autophagy in Leishmania amastigotes may be related to both the increase in parasite load and apoptotic index in inflammatory cells, and with the intensity of the inflammatory response in clinically affected dogs. Thus, our study suggests that apoptotic and autophagy Leishmania within phagocytes may have facilitate the survival of the parasite and it appears to play an important role in the process of Leishmania infection.
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Affiliation(s)
- Barbara Laurice Araújo Verçosa
- Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil; Laboratório de Imunologia Celular, Faculdade de Medicina, Universidade de Brasília, Brasília, Brazil; Faculdade de Ciências da Saúde Pitágoras, Campus Codó, Codó, Maranhão, Brazil.
| | | | - Ana Lys Bezerra Barradas Mineiro
- Departamento de Clínica e Cirurgia Veterinária, Centro de Ciências Agrárias, Universidade Federal do Piauí, Teresina, Piauí, Brazil
| | - Maria Norma Melo
- Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Anilton Cesar Vasconcelos
- Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
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6
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Neuman K, Zhang X, Lejeune BT, Pizzarella D, Vázquez M, Lewis LH, Koppes AN, Koppes RA. Static Magnetic Stimulation and Magnetic Microwires Synergistically Enhance and Guide Neurite Outgrowth. Adv Healthc Mater 2025; 14:e2403956. [PMID: 39568232 PMCID: PMC11773108 DOI: 10.1002/adhm.202403956] [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: 10/11/2024] [Indexed: 11/22/2024]
Abstract
Axonal growth is heavily influenced by topography and biophysical stimuli including magnetic and electrical fields. Despite extensive investigation, the degree of influence and the underlying genetic mechanisms remain poorly understood. Here, a novel approach to guide neurite growth is undertaken using an innovative ferromagnetic composite material - glass-coated magnetic microwire - to furnish a synergistic combination of magnetic and topographical cues. Whole rat dorsal root ganglia (DRG) are cultured under five different conditions: control, static magnetic field, magnetic microwire, static magnetic field + glass fiber, and static magnetic field + magnetic microwire. DRG outgrowth responses under each condition, including total neurite outgrowth and directionality, are compared. The combination of both magnetic stimulation and topography significantly increases total neurite outgrowth compared to the controls. The combination of magnetic stimulation and magnetic microwire lead to a strong directional bias of growth along the microwire, double what is observed with the glass fiber. Next generation RNA sequencing of DRG exposed to static magnetic field + magnetic microwire reveals the downregulation of genes relating to the immune response, interleukin signaling, and signal transduction. These results set the stage for contemplating future biophysical stimulation for axonal guidance and improved understanding of material-tissue interactions.
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Affiliation(s)
- Katelyn Neuman
- Dept. of Chemical EngineeringNortheastern UniversityBostonMA02115USA
| | - Xiaoyu Zhang
- Dept. of Mechanical and Industrial EngineeringNortheastern UniversityBostonMA02115USA
| | - Brian. T. Lejeune
- Dept. of Chemical EngineeringNortheastern UniversityBostonMA02115USA
| | | | - Manuel Vázquez
- Instituto de Ciencia de Materiales de MadridCSICMadrid28049Spain
| | - Laura H. Lewis
- Dept. of Chemical EngineeringNortheastern UniversityBostonMA02115USA
- Dept. of Mechanical and Industrial EngineeringNortheastern UniversityBostonMA02115USA
| | - Abigail N. Koppes
- Dept. of Chemical EngineeringNortheastern UniversityBostonMA02115USA
- Dept. of BioengineeringNortheastern UniversityBostonMA02115USA
- Dept. of BiologyNortheastern UniversityBostonMA02115USA
| | - Ryan A. Koppes
- Dept. of Chemical EngineeringNortheastern UniversityBostonMA02115USA
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7
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Holst-Hansen T, Nielsen PY, Jensen MH, Mandrup-Poulsen T, Trusina A. Tipping-point transition from transient to persistent inflammation in pancreatic islets. NPJ Syst Biol Appl 2024; 10:102. [PMID: 39266581 PMCID: PMC11393080 DOI: 10.1038/s41540-024-00427-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Accepted: 08/19/2024] [Indexed: 09/14/2024] Open
Abstract
Type 2 diabetes (T2D) is associated with a systemic increase in the pro-inflammatory cytokine IL-1β. While transient exposure to low IL-1β concentrations improves insulin secretion and β-cell proliferation in pancreatic islets, prolonged exposure leads to impaired insulin secretion and collective β-cell death. IL-1 is secreted locally by islet-resident macrophages and β-cells; however, it is unknown if and how the two opposing modes may emerge at single islet level. We investigated the duality of IL-1β with a quantitative in silico model of the IL-1 regulatory network in pancreatic islets. We find that the network can produce either transient or persistent IL-1 responses when induced by pro-inflammatory and metabolic cues. This suggests that the duality of IL-1 may be regulated at the single islet level. We use two core feedbacks in the IL-1 regulation to explain both modes: First, a fast positive feedback in which IL-1 induces its own production through the IL-1R/IKK/NF-κB pathway. Second, a slow negative feedback where NF-κB upregulates inhibitors acting at different levels along the IL-1R/IKK/NF-κB pathway-IL-1 receptor antagonist and A20, among others. A transient response ensues when the two feedbacks are balanced. When the positive feedback dominates over the negative, islets transit into the persistent inflammation mode. Consistent with several observations, where the size of islets was implicated in its inflammatory state, we find that large islets and islets with high density of IL-1β amplifying cells are more prone to transit into persistent IL-1β mode. Our results are likely not limited to IL-1β but are general for the combined effect of multiple pro-inflammatory cytokines and chemokines. Generalizing complex regulations in terms of two feedback mechanisms of opposing nature and acting on different time scales provides a number of testable predictions. Taking islet architecture and cellular heterogeneity into consideration, further dynamic monitoring and experimental validation in actual islet samples will be crucial to verify the model predictions and enhance its utility in clinical applications.
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Affiliation(s)
| | - Pernille Yde Nielsen
- Niels Bohr Institute, University of Copenhagen, Copenhagen, Denmark
- Department of Applied Mathematics and Computer Science, Technical University of Denmark, Lyngby, Denmark
| | - Mogens H Jensen
- Niels Bohr Institute, University of Copenhagen, Copenhagen, Denmark.
| | - Thomas Mandrup-Poulsen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
| | - Ala Trusina
- Niels Bohr Institute, University of Copenhagen, Copenhagen, Denmark.
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Fu B, Lou Y, Wu P, Lu X, Xu C. Emerging role of necroptosis, pyroptosis, and ferroptosis in breast cancer: New dawn for overcoming therapy resistance. Neoplasia 2024; 55:101017. [PMID: 38878618 PMCID: PMC11225858 DOI: 10.1016/j.neo.2024.101017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 06/09/2024] [Accepted: 06/10/2024] [Indexed: 07/08/2024]
Abstract
Breast cancer (BC) is one of the primary causes of death in women worldwide. The challenges associated with adverse outcomes have increased significantly, and the identification of novel therapeutic targets has become increasingly urgent. Regulated cell death (RCD) refers to a type of cell death that can be regulated by several different biomacromolecules, which is distinctive from accidental cell death (ACD). In recent years, apoptosis, a representative RCD pathway, has gained significance as a target for BC medications. However, tumor cells exhibit avoidance of apoptosis and result in treatment resistance, which emphasizes further studies devoted to alternative cell death processes, namely necroptosis, pyroptosis, and ferroptosis. Here, in this review, we focus on summarizing the crucial signaling pathways of these RCD in BC. We further discuss the molecular mechanism and potentiality in clinical application of several prospective drugs, nanoparticles, and other small compounds targeting different RCD subroutines of BC. We also discuss the benefits of modulating RCD processes on drug resistance and the advantages of combining RCD modulators with conventional treatments in BC. This review will deepen our understanding of the relationship between RCD and BC, and shed new light on future directions to attack cancer vulnerabilities with RCD modulators for therapeutic purposes.
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Affiliation(s)
- Bifei Fu
- Department of Breast and Thyroid Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang 321000, China
| | - YuMing Lou
- Department of Breast and Thyroid Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang 321000, China
| | - Pu Wu
- Central Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang 321000, China
| | - Xiaofeng Lu
- Department of Breast and Thyroid Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang 321000, China.
| | - Chaoyang Xu
- Department of Breast and Thyroid Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang 321000, China; Central Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang 321000, China.
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9
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Iezhitsa I, Agarwal R, Agarwal P. Unveiling enigmatic essence of Sphingolipids: A promising avenue for glaucoma treatment. Vision Res 2024; 221:108434. [PMID: 38805893 DOI: 10.1016/j.visres.2024.108434] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 05/05/2024] [Accepted: 05/06/2024] [Indexed: 05/30/2024]
Abstract
Treatment of glaucoma, the leading cause of irreversible blindness, remains challenging. The apoptotic loss of retinal ganglion cells (RGCs) in glaucoma is the pathological hallmark. Current treatments often remain suboptimal as they aim to halt RGC loss secondary to reduction of intraocular pressure. The pathophysiological targets for exploring direct neuroprotective approaches, therefore are highly relevant. Sphingolipids have emerged as significant target molecules as they are not only the structural components of various cell constituents, but they also serve as signaling molecules that regulate molecular pathways involved in cell survival and death. Investigations have shown that a critical balance among various sphingolipid species, particularly the ceramide and sphingosine-1-phosphate play a role in deciding the fate of the cell. In this review we briefly discuss the metabolic interconversion of sphingolipid species to get an insight into "sphingolipid rheostat", the dynamic balance among metabolites. Further we highlight the role of sphingolipids in the key pathophysiological mechanisms that lead to glaucomatous loss of RGCs. Lastly, we summarize the potential drug candidates that have been investigated for their neuroprotective effects in glaucoma via their effects on sphingolipid axis.
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10
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Eshraghi R, Shafie D, Raisi A, Goleij P, Mirzaei H. Circular RNAs: a small piece in the heart failure puzzle. Funct Integr Genomics 2024; 24:102. [PMID: 38760573 DOI: 10.1007/s10142-024-01386-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Revised: 04/15/2024] [Accepted: 05/13/2024] [Indexed: 05/19/2024]
Abstract
Cardiovascular disease, specifically heart failure (HF), remains a significant concern in the realm of healthcare, necessitating the development of new treatments and biomarkers. The RNA family consists of various subgroups, including microRNAs, PIWI-interacting RNAs (piRAN) and long non-coding RNAs, which have shown potential in advancing personalized healthcare for HF patients. Recent research suggests that circular RNAs, a lesser-known subgroup of RNAs, may offer a novel set of targets and biomarkers for HF. This review will discuss the biogenesis of circular RNAs, their unique characteristics relevant to HF, their role in heart function, and their potential use as biomarkers in the bloodstream. Furthermore, future research directions in this field will be outlined. The stability of exosomal circRNAs makes them suitable as biomarkers, pathogenic regulators, and potential treatments for cardiovascular diseases such as atherosclerosis, acute coronary syndrome, ischemia/reperfusion injury, HF, and peripheral artery disease. Herein, we summarized the role of circular RNAs and their exosomal forms in HF diseases.
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Affiliation(s)
- Reza Eshraghi
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Davood Shafie
- Heart Failure Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Arash Raisi
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Pouya Goleij
- Department of Genetics, Faculty of Biology, Sana Institute of Higher Education, Sari, Iran.
- USERN Office, Kermanshah University of Medical Sciences, Kermanshah, Iran.
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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11
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Nosik M, Ryzhov K, Kudryavtseva AV, Kuimova U, Kravtchenko A, Sobkin A, Zverev V, Svitich O. Decreased IL-1 β Secretion as a Potential Predictor of Tuberculosis Recurrence in Individuals Diagnosed with HIV. Biomedicines 2024; 12:954. [PMID: 38790916 PMCID: PMC11117744 DOI: 10.3390/biomedicines12050954] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Revised: 04/14/2024] [Accepted: 04/22/2024] [Indexed: 05/26/2024] Open
Abstract
Background: The mechanisms of the formation of immunological competence against tuberculosis (TB), and especially those associated with HIV co-infection, remain poorly understood. However, there is an urgent need for risk recurrence predictive biomarkers, as well as for predictors of successful treatment outcomes. The goal of the study was to identify possible immunological markers of TB recurrence in individuals with HIV/TB co-infection. Methods: The plasma levels of IFN-γ, TNF-α, IL-10, and IL-1β (cytokines which play important roles in the immune activation and protection against Mycobacterium tuberculosis) were measured using ELISA EIA-BEST kits. The cytokine concentrations were determined using a standard curve obtained with the standards provided by the manufacturer of each kit. Results: A total of 211 individuals were enrolled in the study as follows: 62 patients with HIV/TB co-infection, 52 with HIV monoinfection, 52 with TB monoinfection, and 45 healthy donors. Out of the 62 patients with HIV/TB, 75.8% (47) of patients were newly diagnosed with HIV and TB, and 24.2% (15) displayed recurrent TB and were newly diagnosed with HIV. Decreased levels of IFN-γ, TNF-α, and IL-10 were observed in patients with HIV/TB when compared with HIV and TB patients. However, there was no difference in IFN-γ, TNF-α, or IL-10 secretion between both HIV/TB groups. At the same time, an almost 4-fold decrease in Il-1β levels was detected in the HIV/TB group with TB recurrence when compared with the HIV/TB group (p = 0.0001); a 2.8-fold decrease when compared with HIV patients (p = 0.001); and a 2.2-fold decrease with newly diagnosed TB patients (p = 0.001). Conclusions: Significantly decreased Il-1β levels in HIV/TB patients' cohort with secondary TB indicate that this cytokine can be a potential biomarker of TB recurrence.
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Affiliation(s)
- Marina Nosik
- I.I. Mechnikov Institute of Vaccines and Sera, 105064 Moscow, Russia; (K.R.); (V.Z.); (O.S.)
| | - Konstantin Ryzhov
- I.I. Mechnikov Institute of Vaccines and Sera, 105064 Moscow, Russia; (K.R.); (V.Z.); (O.S.)
| | - Asya V. Kudryavtseva
- La Facultad de Ciencias Médicas, Universidad Bernardo O’Higgings-Escuela de Medicina, Santiago 8370993, Chile;
| | - Ulyana Kuimova
- Central Research Institute of Epidemiology, Rospotrebnadzor, 111123 Moscow, Russia; (U.K.); (A.K.)
| | - Alexey Kravtchenko
- Central Research Institute of Epidemiology, Rospotrebnadzor, 111123 Moscow, Russia; (U.K.); (A.K.)
| | - Alexandr Sobkin
- G.A. Zaharyan Moscow Tuberculosis Clinic, Department for Treatment of TB Patients with HIV, 125466 Moscow, Russia;
| | - Vitaly Zverev
- I.I. Mechnikov Institute of Vaccines and Sera, 105064 Moscow, Russia; (K.R.); (V.Z.); (O.S.)
| | - Oxana Svitich
- I.I. Mechnikov Institute of Vaccines and Sera, 105064 Moscow, Russia; (K.R.); (V.Z.); (O.S.)
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12
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Huston HC, Anderson MJ, Fink SL. Pyroptosis and the cellular consequences of gasdermin pores. Semin Immunol 2023; 69:101803. [PMID: 37437353 PMCID: PMC10530493 DOI: 10.1016/j.smim.2023.101803] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 06/13/2023] [Accepted: 06/27/2023] [Indexed: 07/14/2023]
Abstract
The family of gasdermin proteins plays a key role in the host response against external and internal pathogenic signals by mediating the form of inflammatory regulated cell death known as pyroptosis. One of the most well-studied gasdermins within innate immunity is gasdermin D, which is cleaved, oligomerizes, and forms plasma membrane pores. Gasdermin D pores lead to a number of downstream cellular consequences including plasma membrane rupture, or cell lysis. In this review, we describe mechanisms of activation for each of the gasdermins, their cell type specificity and some disease associations. We then discuss downstream consequences of gasdermin pore formation, including cellular mechanisms of membrane repair. Finally, we present some important next steps to better understand pyroptosis and the cellular consequences of gasdermin pore formation.
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Affiliation(s)
- Hanna C Huston
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, United States
| | - Marisa J Anderson
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, United States
| | - Susan L Fink
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, United States.
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13
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Shen S, Shao Y, Li C. Different types of cell death and their shift in shaping disease. Cell Death Discov 2023; 9:284. [PMID: 37542066 PMCID: PMC10403589 DOI: 10.1038/s41420-023-01581-0] [Citation(s) in RCA: 46] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2023] [Revised: 07/16/2023] [Accepted: 07/26/2023] [Indexed: 08/06/2023] Open
Abstract
Cell death is the irreversible stop of life. It is also the basic physiological process of all organisms which involved in the embryonic development, organ maintenance and autoimmunity of the body. In recent years, we have gained more comprehension of the mechanism in cell death and have basically clarified the different types of "programmed cell death", such as apoptosis, necroptosis, autophagy, and pyroptosis, and identified some key genes in these processes. However, in these previous studies, the conversion between different cell death modes and their application in diseases are rarely explored. To sum up, although many valued discoveries have been discovered in the field of cell death in recent years, there are still many unknown problems to be solved in this field. Facts have proved that cell death is a very complex game, and a series of core players have the ability to destroy the delicate balance of the cell environment, from survival to death, from anti-inflammatory to pro-inflammatory. With the thorough research of the complex regulatory mechanism of cell death, there will certainly be exciting new research in this field in the next few years. The sake of this paper is to emphasize the complex mechanism of overturning the balance between different cell fates and provide relevant theoretical basis for the connection between cell death transformation and disease treatment in the future.
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Affiliation(s)
- Sikou Shen
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, 315211, PR China
| | - Yina Shao
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, 315211, PR China
| | - Chenghua Li
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, 315211, PR China.
- Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266071, PR China.
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14
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Ueda H. Non-Vesicular Release of Alarmin Prothymosin α Complex Associated with Annexin-2 Flop-Out. Cells 2023; 12:1569. [PMID: 37371039 DOI: 10.3390/cells12121569] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Accepted: 06/05/2023] [Indexed: 06/29/2023] Open
Abstract
Nuclear protein prothymosin α (ProTα) is a unique member of damage-associated molecular patterns (DAMPs)/alarmins. ProTα prevents neuronal necrosis by causing a cell death mode switch in serum-starving or ischemic/reperfusion models in vitro and in vivo. Underlying receptor mechanisms include Toll-like receptor 4 (TLR4) and Gi-coupled receptor. Recent studies have revealed that the mode of the fatal stress-induced extracellular release of nuclear ProTα from cortical neurons in primary cultures, astrocytes and C6 glioma cells has two steps: ATP loss-induced nuclear release and the Ca2+-mediated formation of a multiple protein complex and its extracellular release. Under the serum-starving condition, ProTα is diffused from the nucleus throughout the cell due to the ATP loss-induced impairment of importin α-mediated nuclear transport. Subsequent mechanisms are all Ca2+-dependent. They include the formation of a protein complex with ProTα, S100A13, p40 Syt-1 and Annexin A2 (ANXA2); the fusion of the protein complex to the plasma membrane via p40 Syt-1-Stx-1 interaction; and TMEM16F scramblase-mediated ANXA2 flop-out. Subsequently, the protein complex is extracellularly released, leaving ANXA2 on the outer cell surface. The ANXA2 is then flipped in by a force of ATP8A2 activity, and the non-vesicular release of protein complex is repeated. Thus, the ANXA2 flop-out could play key roles in a new type of non-vesicular and non-classical release for DAMPs/alarmins, which is distinct from the modes conducted via gasdermin D or mixed-lineage kinase domain-like pseudokinase pores.
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Affiliation(s)
- Hiroshi Ueda
- Department and Institute of Pharmacology, National Defense Medical Center, Nei-hu, Taipei 114201, Taiwan
- Department of Pharmacology and Therapeutic Innovation, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8521, Japan
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15
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Li Y, Jiang Q. Uncoupled pyroptosis and IL-1β secretion downstream of inflammasome signaling. Front Immunol 2023; 14:1128358. [PMID: 37090724 PMCID: PMC10117957 DOI: 10.3389/fimmu.2023.1128358] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Accepted: 03/24/2023] [Indexed: 04/25/2023] Open
Abstract
Inflammasomes are supramolecular platforms that organize in response to various damage-associated molecular patterns and pathogen-associated molecular patterns. Upon activation, inflammasome sensors (with or without the help of ASC) activate caspase-1 and other inflammatory caspases that cleave gasdermin D and pro-IL-1β/pro-IL-18, leading to pyroptosis and mature cytokine secretion. Pyroptosis enables intracellular pathogen niche disruption and intracellular content release at the cost of cell death, inducing pro-inflammatory responses in the neighboring cells. IL-1β is a potent pro-inflammatory regulator for neutrophil recruitment, macrophage activation, and T-cell expansion. Thus, pyroptosis and cytokine secretion are the two main mechanisms that occur downstream of inflammasome signaling; they maintain homeostasis, drive the innate immune response, and shape adaptive immunity. This review aims to discuss the possible mechanisms, timing, consequences, and significance of the two uncoupling preferences downstream of inflammasome signaling. While pyroptosis and cytokine secretion may be usually coupled, pyroptosis-predominant and cytokine-predominant uncoupling are also observed in a stimulus-, cell type-, or context-dependent manner, contributing to the pathogenesis and development of numerous pathological conditions such as cryopyrin-associated periodic syndromes, LPS-induced sepsis, and Salmonella enterica serovar Typhimurium infection. Hyperactive cells consistently release IL-1β without LDH leakage and pyroptotic death, thereby leading to prolonged inflammation, expanding the lifespans of pyroptosis-resistant neutrophils, and hyperactivating stimuli-challenged macrophages, dendritic cells, monocytes, and specific nonimmune cells. Death inflammasome activation also induces GSDMD-mediated pyroptosis with no IL-1β secretion, which may increase lethality in vivo. The sublytic GSDMD pore formation associated with lower expressions of pyroptotic components, GSDMD-mediated extracellular vesicles, or other GSDMD-independent pathways that involve unconventional secretion could contribute to the cytokine-predominant uncoupling; the regulation of caspase-1 dynamics, which may generate various active species with different activities in terms of GSDMD or pro-IL-1β, could lead to pyroptosis-predominant uncoupling. These uncoupling preferences enable precise reactions to different stimuli of different intensities under specific conditions at the single-cell level, promoting cooperative cell and host fate decisions and participating in the pathogen "game". Appropriate decisions in terms of coupling and uncoupling are required to heal tissues and eliminate threats, and further studies exploring the inflammasome tilt toward pyroptosis or cytokine secretion may be helpful.
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16
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González L, Rivera K, Andia ME, Martínez Rodriguez G. The IL-1 Family and Its Role in Atherosclerosis. Int J Mol Sci 2022; 24:17. [PMID: 36613465 PMCID: PMC9820551 DOI: 10.3390/ijms24010017] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 12/09/2022] [Accepted: 12/15/2022] [Indexed: 12/24/2022] Open
Abstract
The IL-1 superfamily of cytokines is a central regulator of immunity and inflammation. The family is composed of 11 cytokines (with agonist, antagonist, and anti-inflammatory properties) and 10 receptors, all tightly regulated through decoy receptor, receptor antagonists, and signaling inhibitors. Inflammation not only is an important physiological response against infection and injury but also plays a central role in atherosclerosis development. Several clinical association studies along with experimental studies have implicated the IL-1 superfamily of cytokines and its receptors in the pathogenesis of cardiovascular disease. Here, we summarize the key features of the IL-1 family, its role in immunity and disease, and how it helps shape the development of atherosclerosis.
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Affiliation(s)
- Leticia González
- Centro de Imágenes Biomédicas—Departamento de Radiología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago 3580000, Chile
- Instituto Milenio de Ingeniería e Inteligencia Artificial Para la Salud, iHEALTH, Pontificia Universidad Católica de Chile, Santiago 7820436, Chile
| | - Katherine Rivera
- Centro de Imágenes Biomédicas—Departamento de Radiología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago 3580000, Chile
- Programa de Doctorado en Ciencias Médicas, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago 3580000, Chile
| | - Marcelo E. Andia
- Centro de Imágenes Biomédicas—Departamento de Radiología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago 3580000, Chile
- Instituto Milenio de Ingeniería e Inteligencia Artificial Para la Salud, iHEALTH, Pontificia Universidad Católica de Chile, Santiago 7820436, Chile
| | - Gonzalo Martínez Rodriguez
- División de Enfermedades Cardiovasculares, Pontificia Universidad Católica de Chile, Santiago 3580000, Chile
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17
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Zhang RN, Sun ZJ, Zhang L. Pyroptosis in inflammatory bone diseases: Molecular insights and targeting strategies. FASEB J 2022; 36:e22670. [PMID: 36412502 DOI: 10.1096/fj.202201229r] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 11/02/2022] [Accepted: 11/11/2022] [Indexed: 11/23/2022]
Abstract
Inflammatory bone diseases include osteoarthritis (OA) and rheumatoid arthritis (RA), which can cause severe bone damage in a chronic inflammation state, putting tremendous pressure on the patients' families and government agencies regarding medical costs. In addition, the complexity of osteoimmunology makes research on these diseases difficult. Hence, it is urgent to determine the potential mechanisms and find effective drugs to target inflammatory bone diseases to reduce the negative effects of these diseases. Recently, pyroptosis, a gasdermin-induced necrotic cell death featuring secretion of pro-inflammatory cytokines and lysis, has become widely known. Based on the effect of pyroptosis on immunity, this process has gradually emerged as a vital component in the etiopathogenesis of inflammatory bone diseases. Herein, we review the characteristics and mechanisms of pyroptosis and then focus on its clinical significance in inflammatory bone diseases. In addition, we summarize the current research progress of drugs targeting pyroptosis to enhance the therapeutic efficacy of inflammatory bone diseases and provide new insights for future directions.
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Affiliation(s)
- Ruo-Nan Zhang
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China.,Department of Endodontics, School and Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Zhi-Jun Sun
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China.,Department of Oral Maxillofacial-Head Neck Oncology, School & Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Lu Zhang
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, China.,Department of Endodontics, School and Hospital of Stomatology, Wuhan University, Wuhan, China
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18
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De Chirico F, Poeta E, Babini G, Piccolino I, Monti B, Massenzio F. New models of Parkinson's like neuroinflammation in human microglia clone 3: Activation profiles induced by INF-γ plus high glucose and mitochondrial inhibitors. Front Cell Neurosci 2022; 16:1038721. [PMID: 36523814 PMCID: PMC9744797 DOI: 10.3389/fncel.2022.1038721] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 11/08/2022] [Indexed: 09/17/2023] Open
Abstract
Microglia activation and neuroinflammation have been extensively studied in murine models of neurodegenerative diseases; however, to overcome the genetic differences between species, a human cell model of microglia able to recapitulate the activation profiles described in patients is needed. Here we developed human models of Parkinson's like neuroinflammation by using the human microglia clone 3 (HMC3) cells, whose activation profile in response to classic inflammatory stimuli has been controversial and reported only at mRNA levels so far. In fact, we showed the increased expression of the pro-inflammatory markers iNOS, Caspase 1, IL-1β, in response to IFN-γ plus high glucose, a non-specific disease stimulus that emphasized the dynamic polarization and heterogenicity of the microglial population. More specifically, we demonstrated the polarization of HMC3 cells through the upregulation of iNOS expression and nitrite production in response to the Parkinson's like stimuli, 6-hydroxidopamine (6-OHDA) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), the latter depending on the NF-κB pathway. Furthermore, we identified inflammatory mediators that promote the pro-inflammatory activation of human microglia as function of different pathways that can simulate the phenotypic transition according to the stage of the pathology. In conclusion, we established and characterized different systems of HMC3 cells activation as in vitro models of Parkinson's like neuroinflammation.
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Affiliation(s)
| | | | | | | | | | - Francesca Massenzio
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
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19
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Wang Q, Li HY, Ling ZM, Chen G, Wei ZY. Inhibition of Schwann cell pannexin 1 attenuates neuropathic pain through the suppression of inflammatory responses. J Neuroinflammation 2022; 19:244. [PMID: 36195881 PMCID: PMC9531429 DOI: 10.1186/s12974-022-02603-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 09/25/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Neuropathic pain is still a challenge for clinical treatment as a result of the comprehensive pathogenesis. Although emerging evidence demonstrates the pivotal role of glial cells in regulating neuropathic pain, the role of Schwann cells and their underlying mechanisms still need to be uncovered. Pannexin 1 (Panx 1), an important membrane channel for the release of ATP and inflammatory cytokines, as well as its activation in central glial cells, contributes to pain development. Here, we hypothesized that Schwann cell Panx 1 participates in the regulation of neuroinflammation and contributes to neuropathic pain. METHODS A mouse model of chronic constriction injury (CCI) in CD1 adult mice or P0-Cre transgenic mice, and in vitro cultured Schwann cells were used. Intrasciatic injection with Panx 1 blockers or the desired virus was used to knock down the expression of Panx 1. Mechanical and thermal sensitivity was assessed using Von Frey and a hot plate assay. The expression of Panx 1 was measured using qPCR, western blotting, and immunofluorescence. The production of cytokines was monitored through qPCR and enzyme-linked immunosorbent assay (ELISA). Panx1 channel activity was detected by ethidium bromide (EB) uptake. RESULTS CCI induced persistent neuroinflammatory responses and upregulation of Panx 1 in Schwann cells. Intrasciatic injection of Panx 1 blockers, carbenoxolone (CBX), probenecid, and Panx 1 mimetic peptide (10Panx) effectively reduced mechanical and heat hyperalgesia. Probenecid treatment of CCI-induced mice significantly reduced Panx 1 expression in Schwann cells, but not in dorsal root ganglion (DRG). In addition, Panx 1 knockdown in Schwann cells with Panx 1 shRNA-AAV in P0-Cre mice significantly reduced CCI-induced neuropathic pain. To determine whether Schwann cell Panx 1 participates in the regulation of neuroinflammation and contributes to neuropathic pain, we evaluated its effect in LPS-treated Schwann cells. We found that inhibition of Panx 1 via CBX and Panx 1-siRNA effectively attenuated the production of selective cytokines, as well as its mechanism of action being dependent on both Panx 1 channel activity and its expression. CONCLUSION In this study, we found that CCI-related neuroinflammation correlates with Panx 1 activation in Schwann cells, indicating that inhibition of Panx 1 channels in Schwann cells reduces neuropathic pain through the suppression of neuroinflammatory responses.
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Affiliation(s)
- Qian Wang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Han-Yang Li
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Zhuo-Min Ling
- Medical School of Nantong University, Nantong, 226001, Jiangsu, China.,Department of Neurology, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu Province, China
| | - Gang Chen
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China. .,Medical School of Nantong University, Nantong, 226001, Jiangsu, China. .,Department of Anesthesiology, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu Province, China.
| | - Zhong-Ya Wei
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China.
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20
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Nguyen NM, Duong MTH, Nguyen PL, Bui BP, Ahn HC, Cho J. Efonidipine Inhibits JNK and NF-κB Pathway to Attenuate Inflammation and Cell Migration Induced by Lipopolysaccharide in Microglial Cells. Biomol Ther (Seoul) 2022; 30:455-464. [PMID: 35993250 PMCID: PMC9424335 DOI: 10.4062/biomolther.2022.076] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 06/15/2022] [Accepted: 06/20/2022] [Indexed: 11/12/2022] Open
Abstract
Efonidipine, a calcium channel blocker, is widely used for the treatment of hypertension and cardiovascular diseases. In our preliminary study using structure-based virtual screening, efonidipine was identified as a potential inhibitor of c-Jun N-terminal kinase 3 (JNK3). Although its antihypertensive effect is widely known, the role of efonidipine in the central nervous system has remained elusive. The present study investigated the effects of efonidipine on the inflammation and cell migration induced by lipopolysaccharide (LPS) using murine BV2 and human HMC3 microglial cell lines and elucidated signaling molecules mediating its effects. We found that the phosphorylations of JNK and its downstream molecule c-Jun in LPS-treated BV2 cells were declined by efonidipine, confirming the finding from virtual screening. In addition, efonidipine inhibited the LPS-induced production of pro-inflammatory factors, including interleukin-1β (IL-1β) and nitric oxide. Similarly, the IL-1β production in LPS-treated HMC3 cells was also inhibited by efonidipine. Efonidipine markedly impeded cell migration stimulated by LPS in both cells. Furthermore, it inhibited the phosphorylation of inhibitor kappa B, thereby suppressing nuclear translocation of nuclear factor-κB (NF-κB) in LPS-treated BV2 cells. Taken together, efonidipine exerts anti-inflammatory and anti-migratory effects in LPS-treated microglial cells through inhibition of the JNK/NF-κB pathway. These findings imply that efonidipine may be a potential candidate for drug repositioning, with beneficial impacts on brain disorders associated with neuroinflammation.
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Affiliation(s)
- Ngoc Minh Nguyen
- College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Goyang 10326, Republic of Korea
| | - Men Thi Hoai Duong
- College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Goyang 10326, Republic of Korea
| | - Phuong Linh Nguyen
- College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Goyang 10326, Republic of Korea
| | - Bich Phuong Bui
- College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Goyang 10326, Republic of Korea
| | - Hee-Chul Ahn
- College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Goyang 10326, Republic of Korea
| | - Jungsook Cho
- College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, Goyang 10326, Republic of Korea
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21
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Wang S, Moreau F, Chadee K. Gasdermins in Innate Host Defense Against Entamoeba histolytica and Other Protozoan Parasites. Front Immunol 2022; 13:900553. [PMID: 35795683 PMCID: PMC9251357 DOI: 10.3389/fimmu.2022.900553] [Citation(s) in RCA: 6] [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: 03/20/2022] [Accepted: 05/23/2022] [Indexed: 11/16/2022] Open
Abstract
Gasdermins (GSDMs) are a group of proteins that are cleaved by inflammatory caspases to induce pore formation in the plasma membrane to cause membrane permeabilization and lytic cell death or pyroptosis. All GSDMs share a conserved structure, containing a cytotoxic N-terminal (NT) pore-forming domain and a C-terminal (CT) repressor domain. Entamoeba histolytica (Eh) in contact with macrophages, triggers outside-in signaling to activate inflammatory caspase-4/1 via the noncanonical and canonical pathway to promote cleavage of gasdermin D (GSDMD). Cleavage of GSDMD removes the auto-inhibition that masks the active pore-forming NT domain in the full-length protein by interactions with GSDM-CT. The cleaved NT-GSDMD monomers then oligomerize to form pores in the plasma membrane to facilitate the release of IL-1β and IL-18 with a measured amount of pyroptosis. Pyroptosis is an effective way to counteract intracellular parasites, which exploit replicative niche to avoid killing. To date, most GSDMs have been verified to perform pore-forming activity and GSDMD-induced pyroptosis is rapidly emerging as a mechanism of anti-microbial host defence. Here, we review our comprehensive and current knowledge on the expression, activation, biological functions, and regulation of GSDMD cleavage with emphases on physiological scenario and related dysfunctions of each GSDM member as executioner of cell death, cytokine secretion and inflammation against Eh and other protozoan parasitic infections.
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Affiliation(s)
| | | | - Kris Chadee
- Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, AB, Canada
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22
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Ohashi A, Uemura Y, Yoshimori M, Wada N, Imadome KI, Yudo K, Koyama T, Shimizu N, Nishio M, Arai A. The Plasma Level of Interleukin-1β Can Be a Biomarker of Angiopathy in Systemic Chronic Active Epstein-Barr Virus Infection. Front Microbiol 2022; 13:874998. [PMID: 35464987 PMCID: PMC9019545 DOI: 10.3389/fmicb.2022.874998] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Accepted: 03/16/2022] [Indexed: 01/12/2023] Open
Abstract
Systemic chronic active Epstein-Barr virus infection (sCAEBV) is an EBV-positive T- or NK-cell neoplasm revealing persistent systemic inflammation. Twenty-five percent of sCAEBV patients accompany angiopathy. It is crucial to clarify the mechanisms of angiopathy development in sCAEBV because angiopathy is one of the main causes of death. Interleukin-1β (IL-1β) is reported to be involved in angiopathy onset. We investigated if IL-1β plays a role as the inducer of angiopathy of sCAEBV. We detected elevated IL-1β levels in four out of 17 sCAEBV patient's plasma. Interestingly, three out of the four had clinically associated angiopathy. None of the other patients with undetectable level of IL-1β had angiopathy. In all patients with high plasma levels of IL-1β and vascular lesions, EBV-infected cells were CD4-positive T cells. In one patient with high plasma IL-1β, the level of IL-1β mRNA of the monocytes was 17.2 times higher than the level of the same patient's EBV-infected cells in peripheral blood. In Ea.hy926 cells, which are the models of vascular endothelial cells, IL-1β inhibited the proliferation and induced the surface coagulation activity. IL-1β is a potent biomarker and a potent therapeutic target to treat sCAEBV accompanying angiopathy.
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Affiliation(s)
- Ayaka Ohashi
- Department of Frontier Medicine, Institute of Medical Science, St. Marianna University School of Medicine, Kanagawa, Japan.,Department of Laboratory Molecular Genetics of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.,Division of Hematology and Oncology, Department of Internal Medicine, St. Marianna University School of Medicine, Kanagawa, Japan
| | - Yu Uemura
- Division of Hematology and Oncology, Department of Internal Medicine, St. Marianna University School of Medicine, Kanagawa, Japan
| | - Mayumi Yoshimori
- Department of Hematological Therapeutics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Naomi Wada
- Department of Advanced Medicine for Viral Infections, National Center for Child Health and Development, Tokyo, Japan
| | - Ken-Ichi Imadome
- Department of Advanced Medicine for Viral Infections, National Center for Child Health and Development, Tokyo, Japan
| | - Kazuo Yudo
- Department of Frontier Medicine, Institute of Medical Science, St. Marianna University School of Medicine, Kanagawa, Japan
| | - Takatoshi Koyama
- Department of Laboratory Molecular Genetics of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.,Department of Hematology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Norio Shimizu
- Center of Stem Cell and Regenerative Medicine, Advanced Multidisciplinary Research Cluster, Institute of Research, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Miwako Nishio
- Department of Laboratory Molecular Genetics of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Ayako Arai
- Division of Hematology and Oncology, Department of Internal Medicine, St. Marianna University School of Medicine, Kanagawa, Japan.,Department of Hematological Therapeutics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
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23
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Anderson ZT, Dawson AD, Slominski AT, Harris ML. Current Insights Into the Role of Neuropeptide Y in Skin Physiology and Pathology. Front Endocrinol (Lausanne) 2022; 13:838434. [PMID: 35418942 PMCID: PMC8996770 DOI: 10.3389/fendo.2022.838434] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 02/21/2022] [Indexed: 11/13/2022] Open
Abstract
Neuropeptide Y is widely distributed within the body and has long been implicated as a contributor to skin disease based on the correlative clinical data. However, until recently, there have been few empirical investigations to determine whether NPY has a pathophysiological role in the skin. Due to appearance-altering phenotypes of atopic dermatitis, psoriasis, and vitiligo, those suffering from these diseases often face multiple forms of negative social attention. This often results in psychological stress, which has been shown to exacerbate inflammatory skin diseases - creating a vicious cycle that perpetuates disease. This has been shown to drive severe depression, which has resulted in suicidal ideation being a comorbidity of these diseases. Herein, we review what is currently known about the associations of NPY with skin diseases and stress. We also review and provide educated guessing what the effects NPY can have in the skin. Inflammatory skin diseases can affect physical appearance to have significant, negative impacts on quality of life. No cure exists for these conditions, highlighting the need for identification of novel proteins/neuropetides, like NPY, that can be targeted therapeutically. This review sets the stage for future investigations into the role of NPY in skin biology and pathology to stimulate research on therapeutic targeting NPY signaling in order to combat inflammatory skin diseases.
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Affiliation(s)
- Zoya T. Anderson
- Department of Biology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Alex D. Dawson
- Department of Biology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Andrzej T. Slominski
- Department of Dermatology, Comprehensive Cancer Center, Cancer Chemoprevention Program, University of Alabama at Birmingham, Birmingham, AL, United States
- Veteran Administration Medical Center, Birmingham, AL, United States
| | - Melissa L. Harris
- Department of Biology, University of Alabama at Birmingham, Birmingham, AL, United States
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24
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Regulation of the release of damage-associated molecular patterns from necroptotic cells. Biochem J 2022; 479:677-685. [PMID: 35293986 DOI: 10.1042/bcj20210604] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 02/23/2022] [Accepted: 02/25/2022] [Indexed: 02/07/2023]
Abstract
Damage-associated molecular patterns (DAMPs) are molecules within living cells that are released when cell membranes are ruptured. Although DAMPs have physiological functions inside the cell, once DAMPs are released extracellularly, they elicit various biological responses, including inflammation, proliferation, tissue damage, and tissue repair, in a context-dependent manner. In past decades, it was assumed that the release of DAMPs was induced by a membrane rupture, caused by passive ATP depletion, or by chemical or mechanical damage to the membrane. However, that concept has been challenged by recent advancements in understanding the regulation of cell death. Necroptosis is a form of regulated cell death, where cells show necrotic morphology. Necroptosis is triggered by death receptors, toll-like receptors, and some viral infections. The membrane rupture is executed by the mixed lineage-like kinase domain-like pseudokinase (MLKL), which forms oligomers that translocate to the plasma membrane during necroptosis. Although the causal relationship between MLKL function and membrane rupture has been extensively investigated, the detailed molecular mechanisms by which oligomerized MLKL induces membrane rupture are not fully understood. This review summarizes recent advances in understanding how MLKL regulates DAMP release and new technologies for visualizing DAMP release at single-cell resolution.
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25
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Chen S, Chi Z, Wang D. Reconstitution System of NLRP3 Inflammasome in HEK293T Cells. METHODS IN MOLECULAR BIOLOGY (CLIFTON, N.J.) 2022; 2459:79-84. [PMID: 35212956 DOI: 10.1007/978-1-0716-2144-8_8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) inflammasome is a cytosolic multimeric protein complex that plays key roles in the host innate immune response to both pathogenic and sterile insults. Here we describe a comprehensive guide to study NLRP3 inflammasome activation in HEK293T cell reconstitution system, which could provide direct biochemical evidence in protein interaction and posttranslational modification of the complex.
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Affiliation(s)
- Sheng Chen
- Institute of Immunology, and Department of Orthopaedic Surgery of the Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.,Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
| | - Zhexu Chi
- Institute of Immunology, and Department of Orthopaedic Surgery of the Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
| | - Di Wang
- Institute of Immunology, and Department of Orthopaedic Surgery of the Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
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26
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Entezari M, Hashemi D, Taheriazam A, Zabolian A, Mohammadi S, Fakhri F, Hashemi M, Hushmandi K, Ashrafizadeh M, Zarrabi A, Ertas YN, Mirzaei S, Samarghandian S. AMPK signaling in diabetes mellitus, insulin resistance and diabetic complications: A pre-clinical and clinical investigation. Biomed Pharmacother 2022; 146:112563. [PMID: 35062059 DOI: 10.1016/j.biopha.2021.112563] [Citation(s) in RCA: 178] [Impact Index Per Article: 59.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Revised: 12/16/2021] [Accepted: 12/19/2021] [Indexed: 12/12/2022] Open
Abstract
Diabetes mellitus (DM) is considered as a main challenge in both developing and developed countries, as lifestyle has changed and its management seems to be vital. Type I and type II diabetes are the main kinds and they result in hyperglycemia in patients and related complications. The gene expression alteration can lead to development of DM and related complications. The AMP-activated protein kinase (AMPK) is an energy sensor with aberrant expression in various diseases including cancer, cardiovascular diseases and DM. The present review focuses on understanding AMPK role in DM. Inducing AMPK signaling promotes glucose in DM that is of importance for ameliorating hyperglycemia. Further investigation reveals the role of AMPK signaling in enhancing insulin sensitivity for treatment of diabetic patients. Furthermore, AMPK upregulation inhibits stress and cell death in β cells that is of importance for preventing type I diabetes development. The clinical studies on diabetic patients have shown the role of AMPK signaling in improving diabetic complications such as brain disorders. Furthermore, AMPK can improve neuropathy, nephropathy, liver diseases and reproductive alterations occurring during DM. For exerting such protective impacts, AMPK signaling interacts with other molecular pathways such as PGC-1α, PI3K/Akt, NOX4 and NF-κB among others. Therefore, providing therapeutics based on AMPK targeting can be beneficial for amelioration of DM.
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Affiliation(s)
- Maliheh Entezari
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Danial Hashemi
- Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Amirhossein Zabolian
- Department of Orthopedics, School of Medicine, 5th Azar Hospital, Golestan University of Medical Sciences, Golestan, Iran
| | - Shima Mohammadi
- Kerman University of Medical Sciences, Kerman 7616913555, Iran
| | - Farima Fakhri
- Kerman University of Medical Sciences, Kerman 7616913555, Iran
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Kiavash Hushmandi
- Department of Food Hygiene and Quality Control, Division of Epidemiology & Zoonosis, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Milad Ashrafizadeh
- Faculty of Engineering and Natural Sciences, Sabanci University, Orta Mahalle, Üniversite Caddesi No. 27, Orhanlı, Tuzla 34956, Istanbul, Turkey; Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla 34956, Istanbul, Turkey
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Sariyer 34396, Istanbul, Turkey
| | - Yavuz Nuri Ertas
- Department of Biomedical Engineering, Erciyes University, Kayseri 38039, Turkey; ERNAM-Nanotechnology Research and Application Center, Erciyes University, Kayseri 38039, Turkey
| | - Sepideh Mirzaei
- Department of Biology, Faculty of Science, Islamic Azad University, Science and Research Branch, Tehran, Iran.
| | - Saeed Samarghandian
- Department of Basic Medical Sciences, Neyshabur University of Medical Sciences, Neyshabur, Iran.
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Fu L, Zhang J, Lin Z, Li Y, Qin G. CircularRNA circ_0071269 knockdown protects against from diabetic cardiomyopathy injury by microRNA-145/gasdermin A axis. Bioengineered 2022; 13:2398-2411. [PMID: 35034587 PMCID: PMC8974193 DOI: 10.1080/21655979.2021.2024688] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 12/27/2021] [Accepted: 12/27/2021] [Indexed: 12/16/2022] Open
Abstract
Circular RNAs (circRNAs) are involved in the development and progression of diabetic cardiomyopathy (DCM). However, the specific function and underlying mechanism of circ_0071269 in DCM remains unclear. In our study, mRNA and miRNA expression was detected by real-time quantitative PCR (qRT-PCR). RNase R and actinomycin D treatment were applied to test the characteristics of circ_0071269. Cell Counting Kit-8 (CCK-8) assay, lactate dehydrogenase (LDH) and enzyme-linked immunosorbent assay (ELISA) kits were performed to determine the cell viability, cell LDH content and interleukin (IL)-1β and IL-18 levels, respectively. Cell death rate was determined by Flow cytometry, and Western blotting was for the protein expression levels. In addition, luciferase reporter and RNA pull-down assays were performed to confirm the binding relationship between miR-145 and circ_0071269 or gasdermin A (GSDMA). Echocardiography, Hematoxylin and Eosin (HE) Staining, and Immunohistochemical (IHC) Staining were performed to evaluate myocardial damage in vivo. We found that circ_0071269 was significantly overexpressed in H9c2 cells upon treatment with high glucose. Knockdown of circ_0071269 promoted cell viability and inhibited the inflammatory response, cytotoxicity, and pyroptosis of H9c2 cells in vitro. Moreover, circ_0071269 sponges miR-145 to upregulate GSDMA. A miR-145 inhibitor antagonized the effects of circ_0071269 knockdown on the cellular functions of H9c2 cells, while the effects of miR-145 were abrogated by the overexpression of GSDMA. Meanwhile, knockdown of circ_0071269 attenuated cardiac dysfunction of DM mice. Hence, circ_0071269 may promote the development of DCM through the miR-145/GSDMA axis and thus provide a novel marker for the treatment of DCM.
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Affiliation(s)
- Lanfang Fu
- Department of Endocrinology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou City, China
- Department of Endocrinology, Haikou Hospital, Affiliated to Xiangya Medical College, Central South University, Haikou, China
| | - Juyun Zhang
- Department of Endocrinology, Haikou Hospital, Affiliated to Xiangya Medical College, Central South University, Haikou, China
| | - Zhu Lin
- Department of Endocrinology, Haikou Hospital, Affiliated to Xiangya Medical College, Central South University, Haikou, China
| | - Yi Li
- Department of Clinical Medicine, Hainan Medical College, Haikou, China
| | - Guijun Qin
- Department of Endocrinology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou City, China
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28
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Mónaco A, Chilibroste S, Yim L, Chabalgoity JA, Moreno M. Inflammasome activation, NLRP3 engagement and macrophage recruitment to tumor microenvironment are all required for Salmonella antitumor effect. Cancer Immunol Immunother 2022; 71:2141-2150. [PMID: 35061085 DOI: 10.1007/s00262-022-03148-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 01/07/2022] [Indexed: 12/13/2022]
Abstract
Salmonella-based cancer therapies show great potential in preclinical models, but for most cases the observed antitumor effect is transient. Understanding the basis of the antitumor efficacy might guide the design of improved strains that elicit long-lasting effects, paving the wave for clinical use. Here, we deepened into the role of macrophages and inflammasome activation in the context of Salmonella anti-melanoma effect. We showed inflammasome activation in melanoma cells upon infection, which correlated with cell surface exposure of gasdermin-D (GSDM-D) and calreticulin (CRT) and High mobility group box 1 protein (HMGB-1) release, suggesting immunogenic cell death, particularly pyroptosis. Salmonella infection upregulated levels of Caspase-11 (Casp11) mRNA, but not Nlrp3 or Nlrc4 mRNA, the only described inflammasome receptors engaged by Salmonella, suggesting that non-canonical inflammasome activation could be occurring in melanoma cells. Intratumoral administration of Salmonella to melanoma-bearing mice elicited local inflammasome activation and interleukin-1β (IL-1β) production together with tumor growth retardation and extended survival in wild type but not Caspase-1/11 (Casp1/11) knockout mice despite similar levels of intratumoral IL-1β in the later. Salmonella antitumor activity was also suppressed in melanoma bearing Nlrp3 knockout mice. Salmonella induced macrophage recruitment to the tumor site and infiltrating cells exhibited inflammasome activation. Depletion experiments confirmed that macrophages are also essential for Salmonella anti-melanoma effect. Intratumoral macrophages showed a marked M2/M1 shift soon after treatment but this inflammatory profile is then lost, which could explain the transient effect of therapy. All in all, our results highlight CASP-1/11 axis and macrophages as essential players in Salmonella-based cancer immunotherapy and suggest a possible target for future interventions.
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Affiliation(s)
- Amy Mónaco
- Departamento de Desarrollo Biotecnológico, Instituto de Higiene, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay
| | - Sofía Chilibroste
- Departamento de Desarrollo Biotecnológico, Instituto de Higiene, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay
| | - Lucía Yim
- Departamento de Desarrollo Biotecnológico, Instituto de Higiene, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay
| | - Jose Alejandro Chabalgoity
- Departamento de Desarrollo Biotecnológico, Instituto de Higiene, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay.
| | - María Moreno
- Departamento de Desarrollo Biotecnológico, Instituto de Higiene, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay.
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29
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Liu J, Zheng J, Xu Y, Cao W, Wang J, Wang B, Zhao L, Zhang X, Liao W. Enriched Environment Attenuates Pyroptosis to Improve Functional Recovery After Cerebral Ischemia/Reperfusion Injury. Front Aging Neurosci 2021; 13:717644. [PMID: 34646128 PMCID: PMC8504677 DOI: 10.3389/fnagi.2021.717644] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 09/01/2021] [Indexed: 12/16/2022] Open
Abstract
Enriched environment (EE) is a complex containing social, cognitive, and motor stimuli. Exposure to EE can promote functional recovery after ischemia/reperfusion (I/R) injury. However, the underlying mechanisms remained unclear. Pyroptosis has recently been identified and demonstrated a significant role in ischemic stroke. The purpose of this study was to explore the effect of EE on neuronal pyroptosis after cerebral I/R injury. In the current study, middle cerebral artery occlusion/reperfusion (MCAO/R) was applied to establish the cerebral I/R injury model. Behavior tests including the modified Neurological Severity Scores (mNSS) and the Morris Water Maze (MWM) were performed. The infarct volume was evaluated by Nissl staining. To evaluate the levels of pyroptosis-related proteins, the levels of GSDMD-N and nod-like receptor protein 1/3 (NLRP1/3) inflammasome-related proteins were examined. The mRNA levels of IL-1β and IL-18 were detected by Quantitative Real-Time PCR (qPCR). The secretion levels of IL-1β and IL-18 were analyzed by ELISA. Also, the expression of p65 and p-p65 were detected. The results showed that EE treatment improved functional recovery, reduced infarct volume, attenuated neuronal pyroptosis after cerebral I/R injury. EE treatment also suppressed the activities of NLRP1/NLRP3 inflammasomes. These may be affected by inhabiting the NF-κB p65 signaling pathway. Our findings suggested that neuronal pyroptosis was probably the neuroprotective mechanism that EE treatment rescued neurological deficits after I/R injury.
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Affiliation(s)
- Jingying Liu
- Department of Rehabilitation Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Jun Zheng
- Department of Rehabilitation Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Yang Xu
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Wenyue Cao
- Department of Rehabilitation Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Jinchen Wang
- Department of Anesthesiology, Zhujiang Hospital of Southern Medical University, Guangzhou, China
| | - Biru Wang
- Department of Rehabilitation Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Linyao Zhao
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Xin Zhang
- Department of Rehabilitation Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Weijing Liao
- Department of Rehabilitation Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
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30
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Diaz-del-Olmo I, Worboys J, Martin-Sanchez F, Gritsenko A, Ambrose AR, Tannahill GM, Nichols EM, Lopez-Castejon G, Davis DM. Internalization of the Membrane Attack Complex Triggers NLRP3 Inflammasome Activation and IL-1β Secretion in Human Macrophages. Front Immunol 2021; 12:720655. [PMID: 34650553 PMCID: PMC8506164 DOI: 10.3389/fimmu.2021.720655] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Accepted: 09/13/2021] [Indexed: 01/01/2023] Open
Abstract
Interleukin 1β (IL-1β) plays a major role in inflammation and is secreted by immune cells, such as macrophages, upon recognition of danger signals. Its secretion is regulated by the inflammasome, the assembly of which results in caspase 1 activation leading to gasdermin D (GSDMD) pore formation and IL-1β release. During inflammation, danger signals also activate the complement cascade, resulting in the formation of the membrane attack complex (MAC). Here, we report that stimulation of LPS-primed human macrophages with sub-lytic levels of MAC results in activation of the NOD-like receptor 3 (NLRP3) inflammasome and GSDMD-mediated IL-1β release. The MAC is first internalized into endosomes and then colocalizes with inflammasome components; adapter protein apoptosis associated speck-like protein containing a CARD (ASC) and NLRP3. Pharmacological inhibitors established that MAC-triggered activation of the NLRP3 inflammasome was dependent on MAC endocytosis. Internalization of the MAC also caused dispersion of the trans-Golgi network. Thus, these data uncover a role for the MAC in activating the inflammasome and triggering IL-1β release in human macrophages.
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Affiliation(s)
- Ines Diaz-del-Olmo
- Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, Lydia Becker Institute of Immunology and Inflammation, The University of Manchester, Manchester, United Kingdom
| | - Jonathan Worboys
- Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, Lydia Becker Institute of Immunology and Inflammation, The University of Manchester, Manchester, United Kingdom
| | - Fatima Martin-Sanchez
- Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, Lydia Becker Institute of Immunology and Inflammation, The University of Manchester, Manchester, United Kingdom
| | - Anna Gritsenko
- Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, Lydia Becker Institute of Immunology and Inflammation, The University of Manchester, Manchester, United Kingdom
| | - Ashley R. Ambrose
- Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, Lydia Becker Institute of Immunology and Inflammation, The University of Manchester, Manchester, United Kingdom
| | | | | | - Gloria Lopez-Castejon
- Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, Lydia Becker Institute of Immunology and Inflammation, The University of Manchester, Manchester, United Kingdom
| | - Daniel M. Davis
- Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, Lydia Becker Institute of Immunology and Inflammation, The University of Manchester, Manchester, United Kingdom
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31
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Rühl S, Broz P. Regulation of Lytic and Non-Lytic Functions of Gasdermin Pores. J Mol Biol 2021; 434:167246. [PMID: 34537232 DOI: 10.1016/j.jmb.2021.167246] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 09/03/2021] [Accepted: 09/10/2021] [Indexed: 12/13/2022]
Abstract
Pyroptosis is a necrotic form of cell death that was initially found to be induced upon activation of inflammatory caspases by inflammasome complexes. Mechanistically, pyroptosis induction requires cleavage of the caspase substrate gasdermin D (GSDMD), and the release of the GSDMD N-terminal fragment, which targets the plasma membrane to form large β-barrel pores. GSDMD shares this pore-forming ability with other gasdermin family members, which induce pyroptosis during infection or upon treatment with chemotherapy drugs. While induction of cell death has been assumed to be the main function of the gasdermin pores, increasing evidence suggests that these pores have non-lytic functions, such as in releasing cytokines or alarmins and in regulating intracellular signaling via ionic fluxes. Here we discuss how gasdermin pore formation is regulated to induce membrane permeabilization or lysis, how gasdermin pores achieve specificity for cargo-release and how cells repair gasdermin-induced damage to the plasma membrane.
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Affiliation(s)
- Sebastian Rühl
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Petr Broz
- Department of Biochemistry, University of Lausanne, 1066 Epalinges, Switzerland.
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32
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Role of S100A8/A9 for Cytokine Secretion, Revealed in Neutrophils Derived from ER-Hoxb8 Progenitors. Int J Mol Sci 2021; 22:ijms22168845. [PMID: 34445548 PMCID: PMC8396251 DOI: 10.3390/ijms22168845] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 08/11/2021] [Accepted: 08/13/2021] [Indexed: 11/17/2022] Open
Abstract
S100A9, a Ca2+-binding protein, is tightly associated to neutrophil pro-inflammatory functions when forming a heterodimer with its S100A8 partner. Upon secretion into the extracellular environment, these proteins behave like damage-associated molecular pattern molecules, which actively participate in the amplification of the inflammation process by recruitment and activation of pro-inflammatory cells. Intracellular functions have also been attributed to the S100A8/A9 complex, notably its ability to regulate nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation. However, the complete functional spectrum of S100A8/A9 at the intracellular level is far from being understood. In this context, we here investigated the possibility that the absence of intracellular S100A8/A9 is involved in cytokine secretion. To overcome the difficulty of genetically modifying neutrophils, we used murine neutrophils derived from wild-type and S100A9−/− Hoxb8 immortalized myeloid progenitors. After confirming that differentiated Hoxb8 neutrophil-like cells are a suitable model to study neutrophil functions, our data show that absence of S100A8/A9 led to a dysregulation of cytokine secretion after lipopolysaccharide (LPS) stimulation. Furthermore, we demonstrate that S100A8/A9-induced cytokine secretion was regulated by the nuclear factor kappa B (NF-κB) pathway. These results were confirmed in human differentiated HL-60 cells, in which S100A9 was inhibited by shRNAs. Finally, our results indicate that the degranulation process could be involved in the regulation of cytokine secretion by S100A8/A9.
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33
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Tonnus W, Belavgeni A, Beuschlein F, Eisenhofer G, Fassnacht M, Kroiss M, Krone NP, Reincke M, Bornstein SR, Linkermann A. The role of regulated necrosis in endocrine diseases. Nat Rev Endocrinol 2021; 17:497-510. [PMID: 34135504 PMCID: PMC8207819 DOI: 10.1038/s41574-021-00499-w] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/22/2021] [Indexed: 12/13/2022]
Abstract
The death of endocrine cells is involved in type 1 diabetes mellitus, autoimmunity, adrenopause and hypogonadotropism. Insights from research on basic cell death have revealed that most pathophysiologically important cell death is necrotic in nature, whereas regular metabolism is maintained by apoptosis programmes. Necrosis is defined as cell death by plasma membrane rupture, which allows the release of damage-associated molecular patterns that trigger an immune response referred to as necroinflammation. Regulated necrosis comes in different forms, such as necroptosis, pyroptosis and ferroptosis. In this Perspective, with a focus on the endocrine environment, we introduce these cell death pathways and discuss the specific consequences of regulated necrosis. Given that clinical trials of necrostatins for the treatment of autoimmune conditions have already been initiated, we highlight the therapeutic potential of such novel therapeutic approaches that, in our opinion, should be tested in endocrine disorders in the future.
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Affiliation(s)
- Wulf Tonnus
- Clinic of Internal Medicine III, Division of Nephrology, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany
| | - Alexia Belavgeni
- Clinic of Internal Medicine III, Division of Nephrology, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany
| | - Felix Beuschlein
- Medizinische Klinik und Poliklinik IV, Hospital of the Ludwig-Maximilian-University Munich, Munich, Germany
- Klinik für Endokrinologie, Diabetologie und Klinische Ernährung, Universitätsspital Zürich, Zürich, Switzerland
| | - Graeme Eisenhofer
- Clinic of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany
| | - Martin Fassnacht
- Clinic of Internal Medicine I, Division of Endocrinology and Diabetology, University Hospital, University of Würzburg, Würzburg, Germany
| | - Matthias Kroiss
- Clinic of Internal Medicine I, Division of Endocrinology and Diabetology, University Hospital, University of Würzburg, Würzburg, Germany
| | - Nils P Krone
- Clinic of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany
- Academic Unit of Child Health, Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
| | - Martin Reincke
- Medizinische Klinik und Poliklinik IV, Hospital of the Ludwig-Maximilian-University Munich, Munich, Germany
| | - Stefan R Bornstein
- Klinik für Endokrinologie, Diabetologie und Klinische Ernährung, Universitätsspital Zürich, Zürich, Switzerland
- Clinic of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany
- Diabetes and Nutritional Sciences, King's College London, London, UK
| | - Andreas Linkermann
- Clinic of Internal Medicine III, Division of Nephrology, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany.
- Biotechnology Center, Technische Universität Dresden, Dresden, Germany.
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Yeung K, Mraz V, Geisler C, Skov L, Bonefeld CM. The role of interleukin-1β in the immune response to contact allergens. Contact Dermatitis 2021; 85:387-397. [PMID: 34324721 DOI: 10.1111/cod.13955] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 07/22/2021] [Accepted: 07/28/2021] [Indexed: 12/29/2022]
Abstract
Interleukin-1β (IL-1β) is an important pro-inflammatory cytokine that has an effect on almost every cell lineage in the body. By blocking IL-1β and investigating the IL-1β signaling pathway, several studies have demonstrated a central role of IL-1β in the response to contact allergens. This review summarizes the current literature regarding the basic immunological mechanisms mediated by IL-1β in the different phases of allergic contact dermatitis (ACD) and highlights potential IL-1β-targeted treatment options, which in the future may be relevant in the treatment of patients with ACD. This review is based primarily on studies using various mouse models and human in vitro studies, since clinical studies on the effect of IL-1β in ACD are lacking.
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Affiliation(s)
- Kelvin Yeung
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Department of Dermatology and Allergy, Copenhagen University Hospital - Herlev and Gentofte, Copenhagen, Denmark
| | - Veronika Mraz
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Carsten Geisler
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Lone Skov
- Department of Dermatology and Allergy, Copenhagen University Hospital - Herlev and Gentofte, Copenhagen, Denmark.,Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Charlotte M Bonefeld
- The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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35
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Yang LY, Bhaskar K, Thompson J, Duval K, Torbey M, Yang Y. Non-invasive vagus nerve stimulation reduced neuron-derived IL-1β and neuroinflammation in acute ischemic rat brain. BRAIN HEMORRHAGES 2021. [DOI: 10.1016/j.hest.2021.06.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
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36
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Kurihara C, Lecuona E, Wu Q, Yang W, Núñez-Santana FL, Akbarpour M, Liu X, Ren Z, Li W, Querrey M, Ravi S, Anderson ML, Cerier E, Sun H, Kelly ME, Abdala-Valencia H, Shilatifard A, Mohanakumar T, Budinger GRS, Kreisel D, Bharat A. Crosstalk between nonclassical monocytes and alveolar macrophages mediates transplant ischemia-reperfusion injury through classical monocyte recruitment. JCI Insight 2021; 6:147282. [PMID: 33621212 PMCID: PMC8026186 DOI: 10.1172/jci.insight.147282] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Accepted: 02/17/2021] [Indexed: 12/24/2022] Open
Abstract
Primary graft dysfunction (PGD) is the predominant cause of early graft loss following lung transplantation. We recently demonstrated that donor pulmonary intravascular nonclassical monocytes (NCM) initiate neutrophil recruitment. Simultaneously, host-origin classical monocytes (CM) permeabilize the vascular endothelium to allow neutrophil extravasation necessary for PGD. Here, we show that a CCL2-CCR2 axis is necessary for CM recruitment. Surprisingly, although intravital imaging and multichannel flow cytometry revealed that depletion of donor NCM abrogated CM recruitment, single cell RNA sequencing identified donor alveolar macrophages (AM) as predominant CCL2 secretors. Unbiased transcriptomic analysis of murine tissues combined with murine KOs and chimeras indicated that IL-1β production by donor NCM was responsible for the early activation of AM and CCL2 release. IL-1β production by NCM was NLRP3 inflammasome dependent and inhibited by treatment with a clinically approved sulphonylurea. Production of CCL2 in the donor AM occurred through IL-1R-dependent activation of the PKC and NF-κB pathway. Accordingly, we show that IL-1β-dependent paracrine interaction between donor NCM and AM leads to recruitment of recipient CM necessary for PGD. Since depletion of donor NCM, IL-1β, or IL-1R antagonism and inflammasome inhibition abrogated recruitment of CM and PGD and are feasible using FDA-approved compounds, our findings may have potential for clinical translation.
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Affiliation(s)
| | | | - Qiang Wu
- Division of Thoracic Surgery and
| | | | | | | | | | - Ziyou Ren
- Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Wenjun Li
- Department of Surgery, Washington University in St. Louis, St. Louis, Missouri, USA
| | | | | | | | | | | | | | - Hiam Abdala-Valencia
- Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Ali Shilatifard
- Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | | | - G R Scott Budinger
- Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Daniel Kreisel
- Department of Surgery, Washington University in St. Louis, St. Louis, Missouri, USA.,Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, Missouri, USA
| | - Ankit Bharat
- Division of Thoracic Surgery and.,Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
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37
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Gowda P, Patrick S, Joshi SD, Kumawat RK, Sen E. Glycyrrhizin prevents SARS-CoV-2 S1 and Orf3a induced high mobility group box 1 (HMGB1) release and inhibits viral replication. Cytokine 2021; 142:155496. [PMID: 33773396 PMCID: PMC7953444 DOI: 10.1016/j.cyto.2021.155496] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Revised: 03/04/2021] [Accepted: 03/05/2021] [Indexed: 12/24/2022]
Abstract
Efforts to understand host factors critical for COVID-19 pathogenesis have identified high mobility group box 1 (HMGB1) to be crucial for regulating susceptibility to SARS-CoV-2. COVID-19 disease severity is correlated with heightened inflammatory responses, and HMGB1 is an important extracellular mediator in inflammation processes. In this study, we evaluated the effect of HMGB1 inhibitor Glycyrrhizin on the cellular perturbations in lung cells expressing SARS-CoV-2 viral proteins. Pyroptosis in lung cells transfected with SARS-CoV-2 S-RBD and Orf3a, was accompanied by elevation of IL-1β and extracellular HMGB1 levels. Glycyrrhizin mitigated viral proteins-induced lung cell pyroptosis and activation of macrophages. Heightened release of proinflammatory cytokines IL-1β, IL-6 and IL-8, as well as ferritin from macrophages cultured in conditioned media from lung cells expressing SARS-CoV-2 S-RBD and Orf3a was attenuated by glycyrrhizin. Importantly, Glycyrrhizin inhibited SARS-CoV-2 replication in Vero E6 cells without exhibiting cytotoxicity at high doses. The dual ability of Glycyrrhizin to concomitantly halt virus replication and dampen proinflammatory mediators might constitute a viable therapeutic option in patients with SARS-CoV-2 infection.
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Affiliation(s)
- Pruthvi Gowda
- National Brain Research Centre, Manesar, Gurugram, Haryana 122 052, India
| | - Shruti Patrick
- National Brain Research Centre, Manesar, Gurugram, Haryana 122 052, India
| | - Shanker Datt Joshi
- National Brain Research Centre, Manesar, Gurugram, Haryana 122 052, India
| | | | - Ellora Sen
- National Brain Research Centre, Manesar, Gurugram, Haryana 122 052, India.
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38
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Stolzer I, Ruder B, Neurath MF, Günther C. Interferons at the crossroad of cell death pathways during gastrointestinal inflammation and infection. Int J Med Microbiol 2021; 311:151491. [PMID: 33662871 DOI: 10.1016/j.ijmm.2021.151491] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 02/03/2021] [Accepted: 02/23/2021] [Indexed: 02/07/2023] Open
Abstract
Interferons (IFNs) are pleiotropic immune-modulatory cytokines that are well known for their essential role in host defense against viruses, bacteria, and other pathogenic microorganisms. They can exert both, protective or destructive functions depending on the microorganism, the targeted tissue and the cellular context. Interferon signaling results in the induction of IFN-stimulated genes (ISGs) influencing different cellular pathways including direct anti-viral/anti-bacterial response, immune-modulation or cell death. Multiple pathways leading to host cell death have been described, and it is becoming clear that depending on the cellular context, IFN-induced cell death can be beneficial for both: host and pathogen. Accordingly, activation or repression of corresponding signaling mechanisms occurs during various types of infection but is also an important pathway for gastrointestinal inflammation and tissue damage. In this review, we summarize the role of interferons at the crossroad of various cell death pathways in the gut during inflammation and infection.
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Affiliation(s)
- Iris Stolzer
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-Universität (FAU), Erlangen, Germany
| | - Barbara Ruder
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-Universität (FAU), Erlangen, Germany
| | - Markus F Neurath
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-Universität (FAU), Erlangen, Germany; Deutsches Zentrum Immuntherapie DZI, Friedrich-Alexander-Universität (FAU), Erlangen, Nürnberg, Germany
| | - Claudia Günther
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-Universität (FAU), Erlangen, Germany.
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Lou J, Zhou Y, Feng Z, Ma M, Yao Y, Wang Y, Deng Y, Wu Y. Caspase-Independent Regulated Necrosis Pathways as Potential Targets in Cancer Management. Front Oncol 2021; 10:616952. [PMID: 33665167 PMCID: PMC7921719 DOI: 10.3389/fonc.2020.616952] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Accepted: 12/29/2020] [Indexed: 12/11/2022] Open
Abstract
Regulated necrosis is an emerging type of cell death independent of caspase. Recently, with increasing findings of regulated necrosis in the field of biochemistry and genetics, the underlying molecular mechanisms and signaling pathways of regulated necrosis are gradually understood. Nowadays, there are several modes of regulated necrosis that are tightly related to cancer initiation and development, including necroptosis, ferroptosis, parthanatos, pyroptosis, and so on. What’s more, accumulating evidence shows that various compounds can exhibit the anti-cancer effect via inducing regulated necrosis in cancer cells, which indicates that caspase-independent regulated necrosis pathways are potential targets in cancer management. In this review, we expand the molecular mechanisms as well as signaling pathways of multiple modes of regulated necrosis. We also elaborate on the roles they play in tumorigenesis and discuss how each of the regulated necrosis pathways could be therapeutically targeted.
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Affiliation(s)
- Jianyao Lou
- Department of General Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yunxiang Zhou
- Department of Surgical Oncology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Zengyu Feng
- Department of General Surgery, Pancreatic Disease Center, Research Institute of Pancreatic Diseases, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Mindi Ma
- Department of Nuclear Medicine, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yihan Yao
- Department of Surgical Oncology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yali Wang
- Department of Surgical Oncology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yongchuan Deng
- Department of Surgical Oncology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yulian Wu
- Department of General Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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40
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Van Den Eeckhout B, Tavernier J, Gerlo S. Interleukin-1 as Innate Mediator of T Cell Immunity. Front Immunol 2021; 11:621931. [PMID: 33584721 PMCID: PMC7873566 DOI: 10.3389/fimmu.2020.621931] [Citation(s) in RCA: 96] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Accepted: 12/08/2020] [Indexed: 12/19/2022] Open
Abstract
The three-signal paradigm tries to capture how the innate immune system instructs adaptive immune responses in three well-defined actions: (1) presentation of antigenic peptides in the context of MHC molecules, which allows for a specific T cell response; (2) T cell co-stimulation, which breaks T cell tolerance; and (3) secretion of polarizing cytokines in the priming environment, thereby specializing T cell immunity. The three-signal model provides an empirical framework for innate instruction of adaptive immunity, but mainly discusses STAT-dependent cytokines in T cell activation and differentiation, while the multi-faceted roles of type I IFNs and IL-1 cytokine superfamily members are often neglected. IL-1α and IL-1β are pro-inflammatory cytokines, produced following damage to the host (release of DAMPs) or upon innate recognition of PAMPs. IL-1 activity on both DCs and T cells can further shape the adaptive immune response with variable outcomes. IL-1 signaling in DCs promotes their ability to induce T cell activation, but also direct action of IL-1 on both CD4+ and CD8+ T cells, either alone or in synergy with prototypical polarizing cytokines, influences T cell differentiation under different conditions. The activities of IL-1 form a direct bridge between innate and adaptive immunity and could therefore be clinically translatable in the context of prophylactic and therapeutic strategies to empower the formation of T cell immunity. Understanding the modalities of IL-1 activity during T cell activation thus could hold major implications for rational development of the next generation of vaccine adjuvants.
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Affiliation(s)
- Bram Van Den Eeckhout
- VIB-UGent Center for Medical Biotechnology, VIB, Ghent, Belgium
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
| | - Jan Tavernier
- VIB-UGent Center for Medical Biotechnology, VIB, Ghent, Belgium
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
- Orionis Biosciences BV, Ghent, Belgium
| | - Sarah Gerlo
- VIB-UGent Center for Medical Biotechnology, VIB, Ghent, Belgium
- Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
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41
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Natural Products as Inducers of Non-Canonical Cell Death: A Weapon against Cancer. Cancers (Basel) 2021; 13:cancers13020304. [PMID: 33467668 PMCID: PMC7830727 DOI: 10.3390/cancers13020304] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 01/09/2021] [Accepted: 01/13/2021] [Indexed: 12/11/2022] Open
Abstract
Simple Summary Anticancer therapeutic approaches based solely on apoptosis induction are often unsuccessful due to the activation of resistance mechanisms. The identification and characterization of compounds capable of triggering non-apoptotic, also called non-canonical cell death pathways, could represent an important strategy that may integrate or offer alternative approaches to the current anticancer therapies. In this review, we critically discuss the promotion of ferroptosis, necroptosis, and pyroptosis by natural compounds as a new anticancer strategy. Abstract Apoptosis has been considered the main mechanism induced by cancer chemotherapeutic drugs for a long time. This paradigm is currently evolving and changing, as increasing evidence pointed out that antitumor agents could trigger various non-canonical or non-apoptotic cell death types. A considerable number of antitumor drugs derive from natural sources, both in their naturally occurring form or as synthetic derivatives. Therefore, it is not surprising that several natural compounds have been explored for their ability to induce non-canonical cell death. The aim of this review is to highlight the potential antitumor effects of natural products as ferroptosis, necroptosis, or pyroptosis inducers. Natural products have proven to be promising non-canonical cell death inducers, capable of overcoming cancer cells resistance to apoptosis. However, as discussed in this review, they often lack a full characterization of their antitumor activity together with an in-depth investigation of their toxicological profile.
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42
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Wolf AJ, Limon JJ, Nguyen C, Prince A, Castro A, Underhill DM. Malassezia spp. induce inflammatory cytokines and activate NLRP3 inflammasomes in phagocytes. J Leukoc Biol 2020; 109:161-172. [PMID: 32941658 DOI: 10.1002/jlb.2ma0820-259r] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Revised: 08/16/2020] [Accepted: 08/25/2020] [Indexed: 12/19/2022] Open
Abstract
Malassezia spp. are common eukaryotic yeasts that colonize mammalian skin. Recently, the authors and others have observed that Malassezia globosa and Malassezia restricta can be found in the intestines in the context of certain diseases, including Crohn's disease and pancreatic cancer. In order to better understand the nature of innate inflammatory responses to these yeasts, inflammatory responses induced by M. restricta and M. globosa in mouse bone marrow-derived Mϕs (BMDM) and dendritic cells (BMDC) are evaluated. While Malassezia yeasts induce proinflammatory cytokine production from both Mϕs and dendritic cells, the levels of production from BMDC were more pronounced. Both M. restricta and M. globosa activated inflammatory cytokine production from BMDC in large part through Dectin2 and CARD9 signaling, although additional receptors appear to be involved in phagocytosis and activation of reactive oxygen production in response to the yeasts. Both M. restricta and M. globosa stimulate production of pro-IL-1β as well as activation of the NLRP3 inflammasome. NLRP3 inflammasome activation by Malassezia fungi requires SYK signaling, potassium efflux and actin rearrangement. Together, the data further the understanding of the coordinated involvement of multiple innate immune receptors in recognizing Malassezia globosa and Malassezia restricta and orchestrating phagocyte inflammatory and antimicrobial responses.
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Affiliation(s)
- Andrea J Wolf
- Department of Biomedical Sciences and the Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Jose J Limon
- Department of Biomedical Sciences and the Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Christopher Nguyen
- Department of Biomedical Sciences and the Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Alexander Prince
- Department of Biomedical Sciences and the Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Anthony Castro
- Department of Biomedical Sciences and the Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - David M Underhill
- Department of Biomedical Sciences and the Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
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43
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Chan AH, Schroder K. Inflammasome signaling and regulation of interleukin-1 family cytokines. J Exp Med 2020; 217:jem.20190314. [PMID: 31611248 PMCID: PMC7037238 DOI: 10.1084/jem.20190314] [Citation(s) in RCA: 259] [Impact Index Per Article: 51.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2019] [Revised: 08/02/2019] [Accepted: 09/11/2019] [Indexed: 12/29/2022] Open
Abstract
Specific IL-1 family cytokines are initially expressed as inactive, cytosolic pro-forms. Chan and Schroder review inflammasome signaling and cell death decisions, mechanisms underpinning IL-1α, IL-1β, IL-18, and IL-37 maturation and release, and the functions of these cytokines in protective and pathological inflammation. Specific IL-1 family cytokines are expressed by cells as cytosolic pro-forms that require cleavage for their activity and cellular release. IL-1β, IL-18, and IL-37 maturation and secretion is governed by inflammatory caspases within signaling platforms called inflammasomes. By inducing pyroptosis, inflammasomes can also drive the release of the alarmin IL-1α. Recent advances have transformed our mechanistic understanding of inflammasome signaling, cell death decisions, and cytokine activation and secretion. Here, we provide an updated view of inflammasome signaling; mechanisms underpinning IL-1α, IL-1β, IL-18, and IL-37 maturation and release; and the functions of these cytokines in protective and pathological inflammation.
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Affiliation(s)
- Amy H Chan
- Institute for Molecular Bioscience and Institute for Molecular Bioscience Centre for Inflammation and Disease Research, The University of Queensland, St. Lucia, Australia
| | - Kate Schroder
- Institute for Molecular Bioscience and Institute for Molecular Bioscience Centre for Inflammation and Disease Research, The University of Queensland, St. Lucia, Australia
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44
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Hoyle C, Redondo-Castro E, Cook J, Tzeng TC, Allan SM, Brough D, Lemarchand E. Hallmarks of NLRP3 inflammasome activation are observed in organotypic hippocampal slice culture. Immunology 2020; 161:39-52. [PMID: 32445196 PMCID: PMC7450173 DOI: 10.1111/imm.13221] [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: 03/20/2020] [Revised: 05/05/2020] [Accepted: 05/18/2020] [Indexed: 12/16/2022] Open
Abstract
Microglial inflammation driven by the NACHT, LRR and PYD domain-containing protein 3 (NLRP3) inflammasome contributes to brain disease and is a therapeutic target. Most mechanistic studies on NLRP3 activation use two-dimensional pure microglial cell culture systems. Here we studied the activation of the NLRP3 inflammasome in organotypic hippocampal slices, which allowed us to investigate microglial NLRP3 activation in a three-dimensional, complex tissue architecture. Toll-like receptor 2 and 4 activation primed microglial inflammasome responses in hippocampal slices by increasing NLRP3 and interleukin-1β expression. Nigericin-induced NLRP3 inflammasome activation was dynamically visualized in microglia through ASC speck formation. Downstream caspase-1 activation, gasdermin D cleavage, pyroptotic cell death and interleukin-1β release were also detected, and these findings were consistent when using different NLRP3 stimuli such as ATP and imiquimod. NLRP3 inflammasome pathway inhibitors were effective in organotypic hippocampal slices. Hence, we have highlighted organotypic hippocampal slice culture as a valuable ex vivo tool to allow the future study of NLRP3 inflammasomes in a representative tissue section, aiding the discovery of further mechanistic insights and drug development.
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Affiliation(s)
- Christopher Hoyle
- Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.,The Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, UK
| | - Elena Redondo-Castro
- Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.,The Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, UK
| | - James Cook
- Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.,The Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, UK
| | - Te-Chen Tzeng
- Immunology and Inflammation, Bristol-Myers Squibb (Celgene Corporation), Cambridge, MA, USA
| | - Stuart M Allan
- Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.,The Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, UK
| | - David Brough
- Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.,The Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, UK
| | - Eloise Lemarchand
- Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.,The Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, UK
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45
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Li S, Lu Y, Ding D, Ma Z, Xing X, Hua X, Xu J. Fibroblast growth factor 2 contributes to the effect of salidroside on dendritic and synaptic plasticity after cerebral ischemia/reperfusion injury. Aging (Albany NY) 2020; 12:10951-10968. [PMID: 32518214 PMCID: PMC7346066 DOI: 10.18632/aging.103308] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Accepted: 04/27/2020] [Indexed: 12/13/2022]
Abstract
Ischemic stroke, a serious neurological disease, is associated with cell death, axonal and dendritic plasticity, and other activities. Anti-inflammatory, anti-apoptotic, promote dendritic and synaptic plasticity are critical therapeutic targets after ischemic stroke. Fibroblast growth factor-2 (FGF2), which is involved in the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/CAMP response element (CRE)-binding protein (CREB) pathway, has been shown to facilitate dendritic and synaptic plasticity. Salidroside (Sal) has been reported to have anti-inflammatory, anti-oxidative, and anti-apoptotic effects; however, the underlying mechanisms of Sal in promoting dendritic and synaptic plasticity remain unclear. Here, the anti-inflammatory, anti-apoptotic, dendritic and synaptic plasticity effects of Sal were investigated in vitro in PC12 cells under oxygen-glucose deprivation/reoxygenation (OGD/R) conditions and in vivo in rats with middle cerebral artery occlusion/reperfusion (MCAO/R). We investigated the role of Sal in promoting dendritic and synaptic plasticity in the ischemic penumbra and whether the FGF2-mediated cAMP/PKA/CREB pathway was involved in this process. The present study demonstrated that Sal could significantly inhibit inflammation and apoptosis, and promote dendritic and synaptic plasticity. Overall, our study suggests that Sal is an effective treatment for ischemic stroke that functions via the FGF2-mediated cAMP/PKA/CREB pathway to promote dendritic and synaptic plasticity.
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Affiliation(s)
- Sisi Li
- School of Rehabilitation Science, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, PR China.,Department of Rehabilitation Medicine, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, PR China
| | - Yechen Lu
- School of Rehabilitation Science, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, PR China.,Department of Rehabilitation Medicine, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, PR China
| | - Daofang Ding
- Department of Rehabilitation Medicine, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, PR China
| | - Zhenzhen Ma
- School of Rehabilitation Science, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, PR China.,Department of Rehabilitation Medicine, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, PR China
| | - Xiangxin Xing
- School of Rehabilitation Science, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, PR China.,Department of Rehabilitation Medicine, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, PR China
| | - Xuyun Hua
- Department of Rehabilitation Medicine, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, PR China.,Department of Trauma and Orthopedics, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, PR China
| | - Jianguang Xu
- School of Rehabilitation Science, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, PR China.,Department of Rehabilitation Medicine, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, PR China.,Department of Hand Surgery, Huashan Hospital, Fudan University, Shanghai 200040, PR China
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46
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Neves AF, Farias FH, de Magalhães SF, Araldi D, Pagliusi M, Tambeli CH, Sartori CR, Lotufo CMDC, Parada CA. Peripheral Inflammatory Hyperalgesia Depends on P2X7 Receptors in Satellite Glial Cells. Front Physiol 2020; 11:473. [PMID: 32523543 PMCID: PMC7261868 DOI: 10.3389/fphys.2020.00473] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Accepted: 04/17/2020] [Indexed: 12/23/2022] Open
Abstract
Peripheral inflammatory hyperalgesia depends on the sensitization of primary nociceptive neurons. Inflammation drives molecular alterations not only locally but also in the dorsal root ganglion (DRG) where interleukin-1 beta (IL-1β) and purinoceptors are upregulated. Activation of the P2X7 purinoceptors by ATP is essential for IL-1β maturation and release. At the DRG, P2X7R are expressed by satellite glial cells (SGCs) surrounding sensory neurons soma. Although SGCs have no projections outside the sensory ganglia these cells affect pain signaling through intercellular communication. Therefore, here we investigated whether activation of P2X7R by ATP and the subsequent release of IL-1β in DRG participate in peripheral inflammatory hyperalgesia. Immunofluorescent images confirmed the expression of P2X7R and IL-1β in SGCs of the DRG. The function of P2X7R was then verified using a selective antagonist, A-740003, or antisense for P2X7R administered in the L5-DRG. Inflammation was induced by CFA, carrageenan, IL-1β, or PGE2 administered in rat's hind paw. Blockage of P2X7R at the DRG reduced the mechanical hyperalgesia induced by CFA, and prevented the mechanical hyperalgesia induced by carrageenan or IL-1β, but not PGE2. It was also found an increase in P2X7 mRNA expression at the DRG after peripheral inflammation. IL-1β production was also increased by inflammatory stimuli in vivo and in vitro, using SGC-enriched cultures stimulated with LPS. In LPS-stimulated cultures, activation of P2X7R by BzATP induced the release of IL-1β, which was blocked by A-740003. In summary, our data suggest that peripheral inflammation leads to the activation of P2X7R expressed by SGCs at the DRG. Then, ATP-induced activation of P2X7R mediates the release of IL-1β from SGC. This evidence places the SGC as an active player in the establishment of peripheral inflammatory hyperalgesia and highlights the importance of the events in DRG for the treatment of inflammatory diseases.
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Affiliation(s)
- Amanda Ferreira Neves
- Department of Structural and Functional Biology, Institute of Biology, University of Campinas, Campinas, Brazil
| | - Felipe Hertzing Farias
- Department of Structural and Functional Biology, Institute of Biology, University of Campinas, Campinas, Brazil
| | | | - Dionéia Araldi
- Department of Structural and Functional Biology, Institute of Biology, University of Campinas, Campinas, Brazil
| | - Marco Pagliusi
- Department of Structural and Functional Biology, Institute of Biology, University of Campinas, Campinas, Brazil
| | - Claudia Herrera Tambeli
- Department of Structural and Functional Biology, Institute of Biology, University of Campinas, Campinas, Brazil
| | - Cesar Renato Sartori
- Department of Structural and Functional Biology, Institute of Biology, University of Campinas, Campinas, Brazil
| | | | - Carlos Amílcar Parada
- Department of Structural and Functional Biology, Institute of Biology, University of Campinas, Campinas, Brazil
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Kawahara Y, Kaneko T, Yoshinaga Y, Arita Y, Nakamura K, Koga C, Yoshimura A, Sakagami R. Effects of Sulfonylureas on Periodontopathic Bacteria-Induced Inflammation. J Dent Res 2020; 99:830-838. [PMID: 32202959 DOI: 10.1177/0022034520913250] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Interleukin-1β (IL-1β) is an inflammatory cytokine produced by monocytes/macrophages and is closely associated with periodontal diseases. The NLRP3 inflammasome is involved in IL-1β activation through pro-IL-1β processing and pyroptotic cell death in bacterial infection. Recently, glyburide, a hypoglycemic sulfonylurea, has been reported to reduce IL-1β activation by suppressing activation of the NLRP3 inflammasome. Therefore, we evaluated the possibility of targeting the NLRP3 inflammasome pathway by glyburide to suppress periodontal pathogen-induced inflammation. THP-1 cells (a human monocyte cell line) were differentiated to macrophage-like cells by treatment with phorbol 12-myristate 13-acetate and stimulated by periodontopathic bacteria, Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, or Fusobacterium nucleatum, in the presence of glyburide. IL-1β and caspase-1 expression in the cells and culture supernatants were analyzed by Western blotting and enzyme-linked immunosorbent assay, and cell death was analyzed by lactate dehydrogenase assay. Stimulation of THP-1 macrophage-like cells with every periodontopathic bacteria induced IL-1β secretion without cell death, which was suppressed by the NLRP3 inhibitor, MCC950, and caspase-1 inhibitor, z-YVAD-FMK. Glyburide treatment suppressed IL-1β expression in culture supernatants and enhanced intracellular IL-1β expression, suggesting that glyburide may have inhibited IL-1β secretion. Subsequently, a periodontitis rat model was generated by injecting periodontal bacteria into the gingiva, which was analyzed histologically. Oral administration of glyburide significantly suppressed the infiltration of inflammatory cells and the number of osteoclasts in the alveolar bone compared with the control. In addition to glyburide, glimepiride was shown to suppress the release of IL-1β from THP-1 macrophage-like cells, whereas other sulfonylureas (tolbutamide and gliclazide) or other hypoglycemic drugs belonging to the biguanide family, such as metformin, failed to suppress IL-1β release. Our results suggest that pharmacological targeting of the NLRP3 pathway may be a strategy for suppressing periodontal diseases.
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Affiliation(s)
- Y Kawahara
- Section of Periodontology, Department of Odontology, Fukuoka Dental College, Fukuoka, Japan
| | - T Kaneko
- Center for Oral Diseases, Fukuoka Dental College, Fukuoka, Japan
| | - Y Yoshinaga
- Section of Periodontology, Department of Odontology, Fukuoka Dental College, Fukuoka, Japan.,Oral Medicine Research Center, Fukuoka Dental College, Fukuoka, Japan
| | - Y Arita
- Section of Periodontology, Department of Odontology, Fukuoka Dental College, Fukuoka, Japan
| | - K Nakamura
- Center for Oral Diseases, Fukuoka Dental College, Fukuoka, Japan
| | - C Koga
- Center for Oral Diseases, Fukuoka Dental College, Fukuoka, Japan
| | - A Yoshimura
- Department of Periodontology and Endodontology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - R Sakagami
- Section of Periodontology, Department of Odontology, Fukuoka Dental College, Fukuoka, Japan
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Nor Arfuzir NN, Agarwal R, Iezhitsa I, Agarwal P, Ismail NM. Magnesium acetyltaurate protects against endothelin-1 induced RGC loss by reducing neuroinflammation in Sprague dawley rats. Exp Eye Res 2020; 194:107996. [PMID: 32156652 DOI: 10.1016/j.exer.2020.107996] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Revised: 02/25/2020] [Accepted: 03/06/2020] [Indexed: 12/22/2022]
Abstract
Endothelin-1 (ET-1), a potent vasoconstrictor, plays a significant role in the pathophysiology of ocular conditions like glaucoma. Glaucoma is characterized by apoptotic loss of retinal ganglion cells (RGCs) and loss of visual fields and is a leading cause of irreversible blindness. In glaucomatous eyes, retinal ischemia causes release of pro-inflammatory mediators such as interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α and promotes activation of transcription factors such as nuclear factor kappa B (NFKB) and c-Jun. Magnesium acetyltaurate (MgAT) has previously been shown to protect against ET-1 induced retinal and optic nerve damage. Current study investigated the mechanisms underlying these effects of MgAT, which so far remain unknown. Sprague dawley rats were intravitreally injected with ET-1 with or without pretreatment with MgAT. Seven days post-injection, retinal expression of IL-1β, IL-6, TNF-α, NFKB and c-Jun protein and genes was determined using multiplex assay, Western blot and PCR. Animals were subjected to retrograde labeling of RGCs to determine the extent of RGC survival. RGC survival was also examined using Brn3A staining. Furthermore, visual functions of rats were determined using Morris water maze. It was observed that pre-treatment with MgAT protects against ET-1 induced increase in the retinal expression of IL-1β, IL-6 and TNF-α proteins and genes. It also protected against ET-1 induced activation of NFKB and c-Jun. These effects of MgAT were associated with greater RGC survival and preservation of visual functions in rats. In conclusion, MgAT prevents ET-1 induced RGC loss and loss of visual functions by suppressing neuroinflammatory reaction in rat retinas.
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Affiliation(s)
- Natasha Najwa Nor Arfuzir
- Center for Neuroscience Research, Faculty of Medicine, Universiti Teknologi MARA Sungai Buloh Campus, Selangor, Malaysia
| | - Renu Agarwal
- School of Medicine, International Medical University, Kuala Lumpur, Malaysia.
| | - Igor Iezhitsa
- Center for Neuroscience Research, Faculty of Medicine, Universiti Teknologi MARA Sungai Buloh Campus, Selangor, Malaysia; Volgograd State Medical University, Research Centre for Innovative Medicines, Volgograd, Russian Federation; Institute for Pathology, Laboratory and Forensic Medicine (I-PPerForM), Universiti Teknologi MARA, Sungai Buloh Campus, Selangor, Malaysia
| | - Puneet Agarwal
- School of Medicine, International Medical University, Kuala Lumpur, Malaysia
| | - Nafeeza Mohd Ismail
- School of Medicine, International Medical University, Kuala Lumpur, Malaysia
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Kumi RO, Soremekun OS, Issahaku AR, Agoni C, Olotu FA, Soliman MES. Exploring the ring potential of 2,4-diaminopyrimidine derivatives towards the identification of novel caspase-1 inhibitors in Alzheimer's disease therapy. J Mol Model 2020; 26:68. [PMID: 32130533 DOI: 10.1007/s00894-020-4319-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2019] [Accepted: 02/03/2020] [Indexed: 12/16/2022]
Abstract
Pro-inflammatory activation of caspase-1 in the neurodegenerative pathway has been associated with age-dependent cognitive impairment and Alzheimer's disease (AD) in humans. A recent report highlighted 2,4-diaminopyrimidine ring as an essential fragment in the inhibition of human caspase-1. However, the role of the ring and its enzyme inhibitory mechanism is not thoroughly investigated at the molecular level. The purpose of this study is therefore in twofold: (1) to understand the enzyme binding mechanism of the 2,4-diaminopyrimidine ring and (2) to search for more potent caspase-1 inhibitors that contain the ring, using integrative per-residue energy decomposition (PRED) pharmacophore modeling. Ligand interaction profile of a reference compound revealed a peculiar hydrogen formation of the amino group of 2,4-diaminopyrimidine with active site residue Arg341, possibly forming the bases for its inhibitory prowess against caspase-1. A generated pharmacophore model for structure-based virtual screening identified compounds, ZINC724667, ZINC09908119, and ZINC09933770, as potential caspase-1 inhibitors that possessed desirable pharmacokinetic and physiochemical properties. Further analyses revealed active site residues, Arg179, Ser236, Cys285, Gln283, Ser339, and Arg341, as crucial to inhibitor binding by stabilizing and forming hydrogen bonds, hydrophobic, and pi-pi interactions with the 2,4-diaminopyrimidine rings. Common interaction patterns of the hits could have accounted for their selective and high-affinity ligand binding, which was characterized by notable disruptions in caspase-1 structural architecture. These compounds could further be explored as potential leads in the development of novel caspase-1 inhibitors.
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Affiliation(s)
- Ransford Oduro Kumi
- Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban, 4001, South Africa
| | - Opeyemi S Soremekun
- Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban, 4001, South Africa
| | - Abdul Rashid Issahaku
- Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban, 4001, South Africa
| | - Clement Agoni
- Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban, 4001, South Africa
| | - Fisayo A Olotu
- Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban, 4001, South Africa
| | - Mahmoud E S Soliman
- Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban, 4001, South Africa.
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50
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Cabău G, Crișan TO, Klück V, Popp RA, Joosten LAB. Urate-induced immune programming: Consequences for gouty arthritis and hyperuricemia. Immunol Rev 2020; 294:92-105. [PMID: 31853991 PMCID: PMC7065123 DOI: 10.1111/imr.12833] [Citation(s) in RCA: 156] [Impact Index Per Article: 31.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Accepted: 12/04/2019] [Indexed: 12/13/2022]
Abstract
Trained immunity is a process in which innate immune cells undergo functional reprogramming in response to pathogens or damage-associated molecules leading to an enhanced non-specific immune response to subsequent stimulation. While this capacity to respond more strongly to stimuli is beneficial for host defense, in some circumstances it can lead to maladaptive programming and chronic inflammation. Gout is characterized by persistent low-grade inflammation and is associated with an increased number of comorbidities. Hyperuricemia is the main risk factor for gout and is linked to the development of comorbidities. Several experimental studies have shown that urate can mechanistically alter the inflammatory capacity of myeloid cells, while observational studies have indicated an association of hyperuricemia to a wide spectrum of common adult inflammatory diseases. In this review, we argue that hyperuricemia is a main culprit in the development of the long-term systemic inflammation seen in gout. We revisit existing evidence for urate-induced transcriptional and epigenetic reprogramming that could lead to an altered functional state of circulating monocytes consisting in enhanced responsiveness and maladaptive immune responses. By discussing specific functional adaptations of monocytes and macrophages induced by soluble urate or monosodium urate crystals and their contribution to inflammation in vitro and in vivo, we further enforce that urate is a metabolite that can induce innate immune memory and we discuss future research and possible new therapeutic approaches for gout and its comorbidities.
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Affiliation(s)
- Georgiana Cabău
- Department of Medical GeneticsIuliu Haţieganu” University of Medicine and PharmacyCluj‐NapocaRomania
| | - Tania O. Crișan
- Department of Medical GeneticsIuliu Haţieganu” University of Medicine and PharmacyCluj‐NapocaRomania
| | - Viola Klück
- Department of Internal MedicineRadboud Institute of Molecular Life Sciences (RIMLS)Radboud University Medical CenterNijmegenThe Netherlands
| | - Radu A. Popp
- Department of Medical GeneticsIuliu Haţieganu” University of Medicine and PharmacyCluj‐NapocaRomania
| | - Leo A. B. Joosten
- Department of Medical GeneticsIuliu Haţieganu” University of Medicine and PharmacyCluj‐NapocaRomania
- Department of Internal MedicineRadboud Institute of Molecular Life Sciences (RIMLS)Radboud University Medical CenterNijmegenThe Netherlands
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