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Zhao G, Zhang HM, Nasseri AR, Yip F, Telkar N, Chen YT, Aghakeshmiri S, Küper C, Lam W, Yang W, Zhao J, Luo H, McManus BM, Yang D. Heart-specific NFAT5 knockout suppresses type I interferon signaling and aggravates coxsackievirus-induced myocarditis. Basic Res Cardiol 2024; 119:1075-1092. [PMID: 38834767 DOI: 10.1007/s00395-024-01058-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 05/20/2024] [Accepted: 05/23/2024] [Indexed: 06/06/2024]
Abstract
Nuclear factor of activated T cells 5 (NFAT5) is an osmosensitive transcription factor that is well-studied in renal but rarely explored in cardiac diseases. Although the association of Coxsackievirus B3 (CVB3) with viral myocarditis is well-established, the role of NFAT5 in this disease remains largely unexplored. Previous research has demonstrated that NFAT5 restricts CVB3 replication yet is susceptible to cleavage by CVB3 proteases. Using an inducible cardiac-specific Nfat5-knockout mouse model, we uncovered that NFAT5-deficiency exacerbates cardiac pathology, worsens cardiac function, elevates viral load, and reduces survival rates. RNA-seq analysis of CVB3-infected mouse hearts revealed the significant impact of NFAT5-deficiency on gene pathways associated with cytokine signaling and inflammation. Subsequent in vitro and in vivo investigation validated the disruption of the cytokine signaling pathway in response to CVB3 infection, evidenced by reduced expression of key cytokines such as interferon β1 (IFNβ1), C-X-C motif chemokine ligand 10 (CXCL10), interleukin 6 (IL6), among others. Furthermore, NFAT5-deficiency hindered the formation of stress granules, leading to a reduction of important stress granule components, including plakophilin-2, a pivotal protein within the intercalated disc, thereby impacting cardiomyocyte structure and function. These findings unveil a novel mechanism by which NFAT5 inhibits CVB3 replication and pathogenesis through the promotion of antiviral type I interferon signaling and the formation of cytoplasmic stress granules, collectively identifying NFAT5 as a new cardio protective protein.
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Affiliation(s)
- Guangze Zhao
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada
- Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, 1081 Burrard Street, Vancouver, B.C, V6Z 1Y6, Canada
| | - Huifang M Zhang
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada
- Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, 1081 Burrard Street, Vancouver, B.C, V6Z 1Y6, Canada
| | - Ali Reza Nasseri
- Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, 1081 Burrard Street, Vancouver, B.C, V6Z 1Y6, Canada
| | - Fione Yip
- Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, 1081 Burrard Street, Vancouver, B.C, V6Z 1Y6, Canada
| | - Nikita Telkar
- British Columbia Cancer Research Centre, University of British Columbia, Vancouver, Canada
- British Columbia Children's Hospital Research Institute, Vancouver, Canada
| | - Yankuan T Chen
- Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, 1081 Burrard Street, Vancouver, B.C, V6Z 1Y6, Canada
| | - Sana Aghakeshmiri
- Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, 1081 Burrard Street, Vancouver, B.C, V6Z 1Y6, Canada
| | - Christoph Küper
- MSH Medical School Hamburg, IMM Institute for Molecular Medicine, Medical University, Hamburg, Germany
| | - Wan Lam
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada
- British Columbia Cancer Research Centre, University of British Columbia, Vancouver, Canada
| | - Wenli Yang
- Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - James Zhao
- Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, 1081 Burrard Street, Vancouver, B.C, V6Z 1Y6, Canada
| | - Honglin Luo
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.
- Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, 1081 Burrard Street, Vancouver, B.C, V6Z 1Y6, Canada.
| | - Bruce M McManus
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.
- Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, 1081 Burrard Street, Vancouver, B.C, V6Z 1Y6, Canada.
| | - Decheng Yang
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.
- Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, 1081 Burrard Street, Vancouver, B.C, V6Z 1Y6, Canada.
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Wang Y, Dong Y, Luan T, Chen Y, Lin L, Li S, Feng D, Wei J, Fei Y, Wang G, Pan J, Wang Y, Zhong Z, Zhao W. TRIM56 restricts Coxsackievirus B infection by mediating the ubiquitination of viral RNA-dependent RNA polymerase 3D. PLoS Pathog 2024; 20:e1012594. [PMID: 39348396 PMCID: PMC11476688 DOI: 10.1371/journal.ppat.1012594] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 10/10/2024] [Accepted: 09/13/2024] [Indexed: 10/02/2024] Open
Abstract
Coxsackievirus B (CVB) is the major causative pathogen for severe diseases such as viral myocarditis, meningitis, and pancreatitis. There is no effective antiviral therapy currently available for CVB infection primarily due to that the pathogenesis of CVB has not been completely understood. Viruses are obligate intracellular pathogens which subvert cellular processes to ensure viral replication. Dysregulation of ubiquitination has been implicated in CVB infection. However, how ubiquitination is involved in CVB infection remains unclear. Here we found that the 3D protein of CVB3, the RNA-dependent RNA polymerase, was modified at K220 by K48-linked polyubiquitination which promoted its degradation through proteasome. Proteomic analysis showed that the E3 ligase TRIM56 was upregulated in CVB3-infected cells, while the majority of TRIMs remained unchanged. Pull-down and immunoprecipitation analyses showed that TRIM56 interacted with CVB3 3D. Immunofluorescence observation showed that viral 3D protein was colocalized with TRIM56. TRIM56 overexpression resulted in enhanced ubiquitination of CVB3 3D and decreased virus yield. Moreover, TRIM56 was cleaved by viral 3C protease in CVB3-infected cells. Taken together, this study demonstrated that TRIM56 mediates the ubiquitination and proteasomal degradation of the CVB3 3D protein. These findings demonstrate that TRIM56 is an intrinsic cellular restriction factor against CVB infection, and enhancing viral protein degradation could be a potential strategy to control CVB infection.
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Affiliation(s)
- Yao Wang
- Department of Cell Biology, Harbin Medical University, Harbin, China
| | - Yanyan Dong
- Department of Cell Biology, Harbin Medical University, Harbin, China
| | - Tian Luan
- Department of Cell Biology, Harbin Medical University, Harbin, China
| | - Yang Chen
- Department of Microbiology, Harbin Medical University, Harbin, China
| | - Lexun Lin
- Teaching Center of Pathogenic Biology, Harbin Medical University, Harbin, China
| | - Siwei Li
- Department of Cell Biology, Harbin Medical University, Harbin, China
| | - Danxiang Feng
- Department of Cell Biology, Harbin Medical University, Harbin, China
| | - Jianwei Wei
- Department of Cell Biology, Harbin Medical University, Harbin, China
| | - Yanru Fei
- Department of Microbiology, Harbin Medical University, Harbin, China
| | - Guangtian Wang
- Teaching Center of Pathogenic Biology, Harbin Medical University, Harbin, China
| | - Jiahui Pan
- Department of Cell Biology, Harbin Medical University, Harbin, China
| | - Yan Wang
- Department of Microbiology, Harbin Medical University, Harbin, China
| | - Zhaohua Zhong
- Department of Microbiology, Harbin Medical University, Harbin, China
| | - Wenran Zhao
- Department of Cell Biology, Harbin Medical University, Harbin, China
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Hu L, Cheng Z, Chu H, Wang W, Jin Y, Yang L. TRIF-dependent signaling and its role in liver diseases. Front Cell Dev Biol 2024; 12:1370042. [PMID: 38694821 PMCID: PMC11061444 DOI: 10.3389/fcell.2024.1370042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2024] [Accepted: 04/08/2024] [Indexed: 05/04/2024] Open
Abstract
TIR domain-containing adaptor inducing IFN-β (TRIF) is a crucial adaptor molecule downstream of toll-like receptors 3 (TLR3) and 4 (TLR4). TRIF directly binds to TLR3 through its TIR domain, while it associates with TLR4 indirectly through the bridge adaptor molecule TRIF-related adaptor molecule (TRAM). TRIF plays a pivotal role in regulating interferon beta 1 (IFN-β) response, nuclear factor kappa B (NF-κB) signaling, apoptosis, and necroptosis signaling mediated by TLR3 and TLR4. It accomplishes these by recruiting and activating various kinases or transcription factors via its distinct domains. In this review, we comprehensively summarize the TRIF-dependent signaling pathways mediated by TLR3 and TLR4, elucidating key target molecules and downstream pathways. Furthermore, we provide an overview of TRIF's impact on several liver disorders, including drug-induced liver injury, ischemia-reperfusion liver injury, autoimmune hepatitis, viral hepatitis, alcohol-associated liver disease (ALD), metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). We also explore its effects on liver steatosis, inflammation, fibrosis, and carcinogenesis. A comprehensive understanding of the TRIF-dependent signaling pathways, as well as the intricate relationship between TRIF and liver diseases, can facilitate the identification of potential drug targets and the development of novel and effective therapeutics against hepatic disorders.
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Affiliation(s)
| | | | | | | | - Yu Jin
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ling Yang
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Kespohl M, Goetzke CC, Althof N, Bredow C, Kelm N, Pinkert S, Bukur T, Bukur V, Grunz K, Kaur D, Heuser A, Mülleder M, Sauter M, Klingel K, Weiler H, Berndt N, Gaida MM, Ruf W, Beling A. TF-FVIIa PAR2-β-Arrestin Signaling Sustains Organ Dysfunction in Coxsackievirus B3 Infection of Mice. Arterioscler Thromb Vasc Biol 2024; 44:843-865. [PMID: 38385286 DOI: 10.1161/atvbaha.123.320157] [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: 09/12/2023] [Accepted: 02/05/2024] [Indexed: 02/23/2024]
Abstract
BACKGROUND Accumulating evidence implicates the activation of G-protein-coupled PARs (protease-activated receptors) by coagulation proteases in the regulation of innate immune responses. METHODS Using mouse models with genetic alterations of the PAR2 signaling platform, we have explored contributions of PAR2 signaling to infection with coxsackievirus B3, a single-stranded RNA virus provoking multiorgan tissue damage, including the heart. RESULTS We show that PAR2 activation sustains correlates of severe morbidity-hemodynamic compromise, aggravated hypothermia, and hypoglycemia-despite intact control of the virus. Following acute viral liver injury, canonical PAR2 signaling impairs the restoration process associated with exaggerated type I IFN (interferon) signatures in response to viral RNA recognition. Metabolic profiling in combination with proteomics of liver tissue shows PAR2-dependent reprogramming of liver metabolism, increased lipid droplet storage, and gluconeogenesis. PAR2-sustained hypodynamic compromise, reprograming of liver metabolism, as well as imbalanced IFN responses are prevented in β-arrestin coupling-deficient PAR2 C-terminal phosphorylation mutant mice. Thus, wiring between upstream proteases and immune-metabolic responses results from biased PAR2 signaling mediated by intracellular recruitment of β-arrestin. Importantly, blockade of the TF (tissue factor)-FVIIa (coagulation factor VIIa) complex capable of PAR2 proteolysis with the NAPc2 (nematode anticoagulant protein c2) mitigated virus-triggered pathology, recapitulating effects seen in protease cleavage-resistant PAR2 mice. CONCLUSIONS These data provide insights into a TF-FVIIa signaling axis through PAR2-β-arrestin coupling that is a regulator of inflammation-triggered tissue repair and hemodynamic compromise in coxsackievirus B3 infection and can potentially be targeted with selective coagulation inhibitors.
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Affiliation(s)
- Meike Kespohl
- Institute of Biochemistry (M.K., C.B., N.K., S.P., A.B.), Charité-Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany
- Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK), partner site Berlin, Germany (M.K., A.B.)
| | - Carl Christoph Goetzke
- Department of Pediatrics, Division of Pulmonology, Immunology and Critical Care Medicine (C.C.G.), Charité-Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany
- Clinician Scientist Program, BIH (Berlin Institute of Health) Academy, BIH, Charité-Universitätsmedizin Berlin, Germany (C.C.G.)
- German Rheumatism Research Center, Leibniz Association, Berlin, Germany (C.C.G.)
| | - Nadine Althof
- German Federal Institute for Risk Assessment, Berlin, Germany (N.A.)
| | - Clara Bredow
- Institute of Biochemistry (M.K., C.B., N.K., S.P., A.B.), Charité-Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany
| | - Nicolas Kelm
- Institute of Biochemistry (M.K., C.B., N.K., S.P., A.B.), Charité-Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany
| | - Sandra Pinkert
- Institute of Biochemistry (M.K., C.B., N.K., S.P., A.B.), Charité-Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany
| | - Thomas Bukur
- Translational Oncology at the University Medical Center of the Johannes Gutenberg University Mainz (TRON), Germany (T.B., V.B.)
| | - Valesca Bukur
- Translational Oncology at the University Medical Center of the Johannes Gutenberg University Mainz (TRON), Germany (T.B., V.B.)
| | - Kristin Grunz
- Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK), partner site Rhein-Main, Germany (K.G., D.K., W.R.)
- University Medical Center Mainz, Center for Thrombosis and Hemostasis, Germany (K.G., D.K., W.R.)
| | - Dilraj Kaur
- Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK), partner site Rhein-Main, Germany (K.G., D.K., W.R.)
- University Medical Center Mainz, Center for Thrombosis and Hemostasis, Germany (K.G., D.K., W.R.)
| | - Arnd Heuser
- Max-Delbrueck-Center for Molecular Medicine, Animal Phenotyping Platform, Berlin, Germany (A.H.)
| | - Michael Mülleder
- Core Facility High-Throughput Mass Spectrometry (M.M.), Charité-Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany
| | - Martina Sauter
- University Hospital Tuebingen, Institute for Pathology and Neuropathology, Cardiopathology, Germany (M.S., K.K.)
| | - Karin Klingel
- University Hospital Tuebingen, Institute for Pathology and Neuropathology, Cardiopathology, Germany (M.S., K.K.)
| | | | - Nikolaus Berndt
- Deutsches Herzzentrum der Charité, Institute of Computer-Assisted Cardiovascular Medicine, Berlin, Germany (N.B.)
- Charité-Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany (N.B.)
- German Institute of Human Nutrition Potsdam-Rehbruecke, Department of Molecular Toxicology, Nuthetal, Germany (N.B.)
| | - Matthias M Gaida
- University Medical Center Mainz, Institute for Pathology, Johannes-Gutenberg-Universität Mainz, Germany (M.M.G.)
- University Medical Center Mainz, Research Center for Immunotherapy, Johannes-Gutenberg-Universität Mainz, Germany (M.M.G.)
- Joint Unit Immunopathology, Institute of Pathology, University Medical Center, Johannes Gutenberg University of Mainz, Germany (M.M.G.)
- TRON, Mainz, Germany (M.M.G.)
| | - Wolfram Ruf
- Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK), partner site Rhein-Main, Germany (K.G., D.K., W.R.)
- University Medical Center Mainz, Center for Thrombosis and Hemostasis, Germany (K.G., D.K., W.R.)
| | - Antje Beling
- Institute of Biochemistry (M.K., C.B., N.K., S.P., A.B.), Charité-Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany
- Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK), partner site Berlin, Germany (M.K., A.B.)
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Zhou J, Lin H, Lv T, Hao J, Zhang H, Sun S, Yang J, Chi J, Guo H. Inappropriate Activation of TLR4/NF-κB is a Cause of Heart Failure. CARDIOVASCULAR INNOVATIONS AND APPLICATIONS 2022. [DOI: 10.15212/cvia.2022.0020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Significance: Heart failure, a disease with extremely high incidence, is closely associated with inflammation and oxidative stress. The Toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) pathway plays an important role in the occurrence and development of heart failure.
Recent advances: Previous studies have shown that TLR4/NF-κB causes heart failure by inducing oxidative stress and inflammation; damaging the endothelia; promoting fibrosis; and inducing myocardial hypertrophy, apoptosis, pyroptosis, and autophagy.
Critical issues: Understanding the pathogenesis of heart failure is essential for the treatment of this disease. In this review, we outline the mechanisms underlying TLR4/NF-κB pathway-mediated heart failure and discuss drugs that alleviate heart failure by regulating the TLR4/NF-κB pathway.
Future directions: During TLR4/NF-κB overactivation, interventions targeting specific receptor antagonists may effectively alleviate heart failure, thus providing a basis for the development of new anti-heart failure drugs.
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Affiliation(s)
- Jiedong Zhou
- Department of Clinical Medicine, School of Medicine, Shaoxing University, Shaoxing, China
| | - Hui Lin
- Department of Cardiology, Shaoxing People’s Hospital Shaoxing Hospital, Shaoxing, China
| | - Tingting Lv
- Department of Clinical Medicine, School of Medicine, Shaoxing University, Shaoxing, China
| | - Jinjin Hao
- Zhejiang University School of Medicine, Hangzhou, China
| | - Hanlin Zhang
- The First Clinical Medical College, Wenzhou Medical University, Wenzhou, China
| | - Shimin Sun
- The First Clinical Medical College, Wenzhou Medical University, Wenzhou, China
| | - Juntao Yang
- Department of Clinical Medicine, School of Medicine, Shaoxing University, Shaoxing, China
| | - Jufang Chi
- Department of Cardiology, Shaoxing People’s Hospital Shaoxing Hospital, Shaoxing, China
| | - Hangyuan Guo
- Department of Clinical Medicine, School of Medicine, Shaoxing University, Shaoxing, China
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6
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Viruses in the Heart: Direct and Indirect Routes to Myocarditis and Heart Failure. Viruses 2021; 13:v13101924. [PMID: 34696354 PMCID: PMC8537553 DOI: 10.3390/v13101924] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 09/09/2021] [Accepted: 09/21/2021] [Indexed: 01/01/2023] Open
Abstract
Viruses are an underappreciated cause of heart failure. Indeed, several types of viral infections carry cardiovascular risks. Understanding shared and unique mechanisms by which each virus compromises heart function is critical to inform on therapeutic interventions. This review describes how the key viruses known to lead to cardiac dysfunction operate. Both direct host-damaging mechanisms and indirect actions on the immune systems are discussed. As viral myocarditis is a key pathologic driver of heart failure in infected individuals, this review also highlights the role of cytokine storms and inflammation in virus-induced cardiomyopathy.
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Bode MF, Schmedes CM, Egnatz GJ, Bharathi V, Hisada YM, Martinez D, Kawano T, Weithauser A, Rosenfeldt L, Rauch U, Palumbo JS, Antoniak S, Mackman N. Cell type-specific roles of PAR1 in Coxsackievirus B3 infection. Sci Rep 2021; 11:14264. [PMID: 34253819 PMCID: PMC8275627 DOI: 10.1038/s41598-021-93759-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Accepted: 06/14/2021] [Indexed: 12/14/2022] Open
Abstract
Protease-activated receptor 1 (PAR1) is widely expressed in humans and mice, and is activated by a variety of proteases, including thrombin. Recently, we showed that PAR1 contributes to the innate immune response to viral infection. Mice with a global deficiency of PAR1 expressed lower levels of CXCL10 and had increased Coxsackievirus B3 (CVB3)-induced myocarditis compared with control mice. In this study, we determined the effect of cell type-specific deletion of PAR1 in cardiac myocytes (CMs) and cardiac fibroblasts (CFs) on CVB3-induced myocarditis. Mice lacking PAR1 in either CMs or CFs exhibited increased CVB3 genomes, inflammatory infiltrates, macrophages and inflammatory mediators in the heart and increased CVB3-induced myocarditis compared with wild-type controls. Interestingly, PAR1 enhanced poly I:C induction of CXCL10 in rat CFs but not in rat neonatal CMs. Importantly, activation of PAR1 reduced CVB3 replication in murine embryonic fibroblasts and murine embryonic cardiac myocytes. In addition, we showed that PAR1 reduced autophagy in murine embryonic fibroblasts and rat H9c2 cells, which may explain how PAR1 reduces CVB3 replication. These data suggest that PAR1 on CFs protects against CVB3-induced myocarditis by enhancing the anti-viral response whereas PAR1 on both CMs and fibroblasts inhibits viral replication.
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Affiliation(s)
- Michael F Bode
- Division of Cardiology, Department of Medicine, UNC McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Division of Cardiology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Division of Cardiology, Department of Medicine, Lahey Hospital & Medical Center, Burlington, MA, USA
| | - Clare M Schmedes
- Division of Hematology, Department of Medicine, UNC Blood Research Center, University of North Carolina at Chapel Hill, 116 Manning Drive CB 7035, 8004B Mary Ellen Jones Building, Chapel Hill, NC, 27599, USA
| | - Grant J Egnatz
- Division of Hematology, Department of Medicine, UNC Blood Research Center, University of North Carolina at Chapel Hill, 116 Manning Drive CB 7035, 8004B Mary Ellen Jones Building, Chapel Hill, NC, 27599, USA
| | - Vanthana Bharathi
- Division of Hematology, Department of Medicine, UNC Blood Research Center, University of North Carolina at Chapel Hill, 116 Manning Drive CB 7035, 8004B Mary Ellen Jones Building, Chapel Hill, NC, 27599, USA
| | - Yohei M Hisada
- Division of Hematology, Department of Medicine, UNC Blood Research Center, University of North Carolina at Chapel Hill, 116 Manning Drive CB 7035, 8004B Mary Ellen Jones Building, Chapel Hill, NC, 27599, USA
| | - David Martinez
- Division of Hematology, Department of Medicine, UNC Blood Research Center, University of North Carolina at Chapel Hill, 116 Manning Drive CB 7035, 8004B Mary Ellen Jones Building, Chapel Hill, NC, 27599, USA
| | - Tomohiro Kawano
- Division of Hematology, Department of Medicine, UNC Blood Research Center, University of North Carolina at Chapel Hill, 116 Manning Drive CB 7035, 8004B Mary Ellen Jones Building, Chapel Hill, NC, 27599, USA
| | - Alice Weithauser
- CharitéCentrum 11 Cardiovascular Diseases, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany
| | - Leah Rosenfeldt
- Cancer and Blood Disease Institute, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Ursula Rauch
- CharitéCentrum 11 Cardiovascular Diseases, Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany
| | - Joseph S Palumbo
- Cancer and Blood Disease Institute, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Silvio Antoniak
- Department of Pathology and Laboratory Medicine, UNC Blood Research Center, UNC McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Nigel Mackman
- Division of Hematology, Department of Medicine, UNC Blood Research Center, University of North Carolina at Chapel Hill, 116 Manning Drive CB 7035, 8004B Mary Ellen Jones Building, Chapel Hill, NC, 27599, USA.
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Favere K, Bosman M, Klingel K, Heymans S, Van Linthout S, Delputte PL, De Sutter J, Heidbuchel H, Guns PJ. Toll-Like Receptors: Are They Taking a Toll on the Heart in Viral Myocarditis? Viruses 2021; 13:v13061003. [PMID: 34072044 PMCID: PMC8227433 DOI: 10.3390/v13061003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 05/23/2021] [Accepted: 05/24/2021] [Indexed: 12/30/2022] Open
Abstract
Myocarditis is an inflammatory disease of the heart with viral infections being the most common aetiology. Its complex biology remains poorly understood and its clinical management is one of the most challenging in the field of cardiology. Toll-like receptors (TLRs), a family of evolutionarily conserved pattern recognition receptors, are increasingly known to be implicated in the pathophysiology of viral myocarditis. Their central role in innate and adaptive immune responses, and in the inflammatory reaction that ensues, indeed makes them prime candidates to profoundly affect every stage of the disease process. This review describes the pathogenesis and pathophysiology of viral myocarditis, and scrutinises the role of TLRs in every phase. We conclude with directions for future research in this field.
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Affiliation(s)
- Kasper Favere
- Laboratory of Physiopharmacology, GENCOR, University of Antwerp, 2610 Antwerp, Belgium; (M.B.); (P.-J.G.)
- Research Group Cardiovascular Diseases, GENCOR, University of Antwerp, 2610 Antwerp, Belgium;
- Department of Cardiology, Antwerp University Hospital, 2650 Antwerp, Belgium
- Department of Internal Medicine, Ghent University, 9000 Ghent, Belgium;
- Correspondence:
| | - Matthias Bosman
- Laboratory of Physiopharmacology, GENCOR, University of Antwerp, 2610 Antwerp, Belgium; (M.B.); (P.-J.G.)
| | - Karin Klingel
- Cardiopathology, Institute for Pathology, University Hospital Tuebingen, 72076 Tuebingen, Germany;
| | - Stephane Heymans
- Department of Cardiology, Maastricht University, 6229 ER Maastricht, The Netherlands;
- Centre for Molecular and Vascular Biology, KU Leuven, 3000 Leuven, Belgium
| | - Sophie Van Linthout
- BIH Center for Regenerative Therapies (BCRT), Berlin Institute of Health (BIH) at Charité, Universitätsmedizin Berlin, 10117 Berlin, Germany;
- German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, 10785 Berlin, Germany
| | - Peter L. Delputte
- Laboratory of Microbiology, Parasitology and Hygiene, University of Antwerp, 2610 Antwerp, Belgium;
| | - Johan De Sutter
- Department of Internal Medicine, Ghent University, 9000 Ghent, Belgium;
| | - Hein Heidbuchel
- Research Group Cardiovascular Diseases, GENCOR, University of Antwerp, 2610 Antwerp, Belgium;
- Department of Cardiology, Antwerp University Hospital, 2650 Antwerp, Belgium
| | - Pieter-Jan Guns
- Laboratory of Physiopharmacology, GENCOR, University of Antwerp, 2610 Antwerp, Belgium; (M.B.); (P.-J.G.)
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Khawaja A, Bromage DI. The innate immune response in myocarditis. Int J Biochem Cell Biol 2021; 134:105973. [PMID: 33831592 DOI: 10.1016/j.biocel.2021.105973] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 03/12/2021] [Accepted: 03/31/2021] [Indexed: 12/14/2022]
Abstract
Acute myocarditis is an inflammatory condition of the heart characterised by cellular injury and the influx of leucocytes, including neutrophils, monocytes, macrophages and lymphocytes. While this response is vital for tissue repair, excessive scar deposition and maladaptive ventricular remodelling can result in a legacy of heart failure. It is increasingly recognised as a clinical phenomenon due, in part, to increased availability of cardiac magnetic resonance imaging in patients presenting with chest pain in the absence of significant coronary artery disease. Emerging epidemiological evidence has associated myocarditis with poor outcomes in the context of left ventricular impairment, and even when the left ventricle is preserved outcomes are less benign than once thought. Despite this, our understanding of the contribution of the inflammatory response to the pathophysiology of acute myocarditis lags behind that of acute myocardial infarction, which is the vanguard cardiovascular condition for inflammation research. We recently reviewed monocyte and macrophage phenotype and function in acute myocardial infarction, concluding that their plasticity and heterogeneity might account for conflicting evidence from attempts to target specific leucocyte subpopulations. Here, we revise our understanding of myocardial inflammation, which is predominantly derived from myocardial infarction research, review experimental evidence for the immune response in acute myocarditis, focusing on innate immunity, and discuss potential future directions for immunotherapy research in acute myocarditis.
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Affiliation(s)
- Abdullah Khawaja
- School of Cardiovascular Medicine and Sciences, King's College London British Heart Foundation Centre of Excellence, James Black Centre, 125 Coldharbour Lane, London, SE5 9NU, UK
| | - Daniel I Bromage
- School of Cardiovascular Medicine and Sciences, King's College London British Heart Foundation Centre of Excellence, James Black Centre, 125 Coldharbour Lane, London, SE5 9NU, UK.
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10
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Aboudounya MM, Heads RJ. COVID-19 and Toll-Like Receptor 4 (TLR4): SARS-CoV-2 May Bind and Activate TLR4 to Increase ACE2 Expression, Facilitating Entry and Causing Hyperinflammation. Mediators Inflamm 2021; 2021:8874339. [PMID: 33505220 PMCID: PMC7811571 DOI: 10.1155/2021/8874339] [Citation(s) in RCA: 236] [Impact Index Per Article: 59.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 12/16/2020] [Accepted: 12/22/2020] [Indexed: 01/08/2023] Open
Abstract
Causes of mortality from COVID-19 include respiratory failure, heart failure, and sepsis/multiorgan failure. TLR4 is an innate immune receptor on the cell surface that recognizes pathogen-associated molecular patterns (PAMPs) including viral proteins and triggers the production of type I interferons and proinflammatory cytokines to combat infection. It is expressed on both immune cells and tissue-resident cells. ACE2, the reported entry receptor for SARS-CoV-2, is only present on ~1-2% of the cells in the lungs or has a low pulmonary expression, and recently, the spike protein has been proposed to have the strongest protein-protein interaction with TLR4. Here, we review and connect evidence for SARS-CoV-1 and SARS-CoV-2 having direct and indirect binding to TLR4, together with other viral precedents, which when combined shed light on the COVID-19 pathophysiological puzzle. We propose a model in which the SARS-CoV-2 spike glycoprotein binds TLR4 and activates TLR4 signalling to increase cell surface expression of ACE2 facilitating entry. SARS-CoV-2 also destroys the type II alveolar cells that secrete pulmonary surfactants, which normally decrease the air/tissue surface tension and block TLR4 in the lungs thus promoting ARDS and inflammation. Furthermore, SARS-CoV-2-induced myocarditis and multiple-organ injury may be due to TLR4 activation, aberrant TLR4 signalling, and hyperinflammation in COVID-19 patients. Therefore, TLR4 contributes significantly to the pathogenesis of SARS-CoV-2, and its overactivation causes a prolonged or excessive innate immune response. TLR4 appears to be a promising therapeutic target in COVID-19, and since TLR4 antagonists have been previously trialled in sepsis and in other antiviral contexts, we propose the clinical trial testing of TLR4 antagonists in the treatment of severe COVID-19. Also, ongoing clinical trials of pulmonary surfactants in COVID-19 hold promise since they also block TLR4.
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Affiliation(s)
- Mohamed M. Aboudounya
- Department of Cardiology, The Rayne Institute, St Thomas' Hospital, British Heart Foundation Centre of Research Excellence, School of Cardiovascular Medicine and Sciences, King's College London, UK
| | - Richard J. Heads
- Department of Cardiology, The Rayne Institute, St Thomas' Hospital, British Heart Foundation Centre of Research Excellence, School of Cardiovascular Medicine and Sciences, King's College London, UK
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11
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Host genetic susceptibility to viral infections: the role of type I interferon induction. Genes Immun 2020; 21:365-379. [PMID: 33219336 PMCID: PMC7677911 DOI: 10.1038/s41435-020-00116-2] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 10/27/2020] [Accepted: 10/29/2020] [Indexed: 02/08/2023]
Abstract
The innate immune response is the major front line of defense against viral infections. It involves hundreds of genes with antiviral properties which expression is induced by type I interferons (IFNs) and are therefore called interferon stimulated genes (ISGs). Type I IFNs are produced after viral recognition by pathogen recognition receptors, which trigger a cascade of activation events. Human and mouse studies have shown that defective type I IFNs induction may hamper the ability to control viral infections. In humans, moderate to high-effect variants have been identified in individuals with particularly severe complications following viral infection. In mice, functional studies using knock-out alleles have revealed the specific role of most genes of the IFN pathway. Here, we review the role of the molecular partners of the type I IFNs induction pathway and their implication in the control of viral infections and of their complications.
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12
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Tschöpe C, Van Linthout S, Jäger S, Arndt R, Trippel T, Müller I, Elsanhoury A, Rutschow S, Anker SD, Schultheiss HP, Pauschinger M, Spillmann F, Pappritz K. Modulation of the acute defence reaction by eplerenone prevents cardiac disease progression in viral myocarditis. ESC Heart Fail 2020; 7:2838-2852. [PMID: 32662949 PMCID: PMC7405199 DOI: 10.1002/ehf2.12887] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 06/04/2020] [Accepted: 06/24/2020] [Indexed: 12/19/2022] Open
Abstract
Aims Left ventricular (LV) dysfunction in viral myocarditis is attributed to myocardial inflammation and fibrosis, inducing acute and long‐time cardiac damage. Interventions are not established. On the basis of the link between inflammation, fibrosis, aldosterone, and extracellular matrix regulation, we aimed to investigate the effect of an early intervention with the mineralocorticoid receptor antagonist (MRA) eplerenone on cardiac remodelling in a murine model of persistent coxsackievirus B3 (CVB3)‐induced myocarditis. Methods and results SWR/J mice were infected with 5 × 104 plaque‐forming units of CVB3 (Nancy strain) and daily treated either with eplerenone (200 mg/kg body weight) or with placebo starting from Day 1. At Day 8 or 28 post infection, mice were haemodynamically characterized and subsequently sacrificed for immunohistological and molecular biology analyses. Eplerenone did not influence CVB3 load. Already at Day 8, 1.8‐fold (P < 0.05), 1.4‐fold (P < 0.05), 3.2‐fold (P < 0.01), and 2.1‐fold (P < 0.001) reduction in LV intercellular adhesion molecule 1 expression, presence of monocytes/macrophages, oxidative stress, and apoptosis, respectively, was observed in eplerenone‐treated vs. untreated CVB3‐infected mice. In vitro, eplerenone led to 1.4‐fold (P < 0.01) and 1.2‐fold (P < 0.01) less CVB3‐induced cardiomyocyte oxidative stress and apoptosis. Furthermore, collagen production was 1.1‐fold (P < 0.05) decreased in cardiac fibroblasts cultured with medium of eplerenone‐treated vs. untreated CVB3‐infected HL‐1 cardiomyocytes. These ameliorations were in vivo translated into prevention of cardiac fibrosis, as shown by 1.4‐fold (P < 0.01) and 2.1‐fold (P < 0.001) lower collagen content in the LV of eplerenone‐treated vs. untreated CVB3‐infected mice at Days 8 and 28, respectively. This resulted in an early and long‐lasting improvement of LV dimension and function, as indicated by reduced LV end‐systolic volume and end‐diastolic volume, and an increase in LV contractility (dP/dtmax) and LV relaxation (dP/dtmin), respectively (P < 0.05). Conclusions Early intervention with the MRA eplerenone modulates the acute host and defence reaction and prevents cardiac disease progression in experimental CVB3‐induced myocarditis without aggravation of viral load. The findings advocate for an initiation of therapy of viral myocarditis as early as possible, even before the onset of inflammation‐induced myocardial dysfunction. This may also have implications for coronavirus disease‐19 therapy.
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Affiliation(s)
- Carsten Tschöpe
- Berlin Institute of Health Center for Regenerative Therapies and Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin Berlin, Berlin, Germany.,German Center for Cardiovascular Research (DZHK), Partner site Berlin, Berlin, Germany.,Department of Cardiology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum (CVK), Berlin, Germany
| | - Sophie Van Linthout
- Berlin Institute of Health Center for Regenerative Therapies and Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin Berlin, Berlin, Germany.,German Center for Cardiovascular Research (DZHK), Partner site Berlin, Berlin, Germany
| | - Sebastian Jäger
- Department of Cardiology, Alexianer Hospital Hedwigshöhe, Berlin, Germany
| | - Robert Arndt
- Department of Emergency Medicine, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin (CBF), Berlin, Germany
| | - Tobias Trippel
- Department of Cardiology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum (CVK), Berlin, Germany
| | - Irene Müller
- Berlin Institute of Health Center for Regenerative Therapies and Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin Berlin, Berlin, Germany.,German Center for Cardiovascular Research (DZHK), Partner site Berlin, Berlin, Germany
| | - Ahmed Elsanhoury
- Berlin Institute of Health Center for Regenerative Therapies and Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin Berlin, Berlin, Germany.,German Center for Cardiovascular Research (DZHK), Partner site Berlin, Berlin, Germany
| | - Susanne Rutschow
- Department of Cardiology, Angiology Johanniter-Kliniken, Stendal, Germany
| | - Stefan D Anker
- Berlin Institute of Health Center for Regenerative Therapies and Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin Berlin, Berlin, Germany.,German Center for Cardiovascular Research (DZHK), Partner site Berlin, Berlin, Germany.,Department of Cardiology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum (CVK), Berlin, Germany
| | | | - Matthias Pauschinger
- Department of Cardiology, Paracelsus University, Klinikum Nürnberg, Nürnberg, Germany
| | - Frank Spillmann
- Department of Cardiology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum (CVK), Berlin, Germany
| | - Kathleen Pappritz
- Berlin Institute of Health Center for Regenerative Therapies and Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin Berlin, Berlin, Germany.,German Center for Cardiovascular Research (DZHK), Partner site Berlin, Berlin, Germany
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13
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Lavine KJ, Pinto AR, Epelman S, Kopecky BJ, Clemente-Casares X, Godwin J, Rosenthal N, Kovacic JC. The Macrophage in Cardiac Homeostasis and Disease: JACC Macrophage in CVD Series (Part 4). J Am Coll Cardiol 2019; 72:2213-2230. [PMID: 30360829 DOI: 10.1016/j.jacc.2018.08.2149] [Citation(s) in RCA: 166] [Impact Index Per Article: 27.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2018] [Revised: 07/13/2018] [Accepted: 08/03/2018] [Indexed: 12/24/2022]
Abstract
Macrophages are integral components of cardiac tissue and exert profound effects on the healthy and diseased heart. Paradigm shifting studies using advanced molecular techniques have revealed significant complexity within these macrophage populations that reside in the heart. In this final of a 4-part review series covering the macrophage in cardiovascular disease, the authors review the origins, dynamics, cell surface markers, and respective functions of each cardiac macrophage subset identified to date, including in the specific scenarios of myocarditis and after myocardial infarction. Looking ahead, a deeper understanding of the diverse and often dichotomous functions of cardiac macrophages will be essential for the development of targeted therapies to mitigate injury and orchestrate recovery of the diseased heart. Moreover, as macrophages are critical for cardiac healing, they are an emerging focus for therapeutic strategies aimed at minimizing cardiomyocyte death, ameliorating pathological cardiac remodeling, and for treating heart failure and after myocardial infarction.
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Affiliation(s)
- Kory J Lavine
- Division of Cardiovascular Medicine, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri; Center for Cardiovascular Research, Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri; Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri; Department of Immunology and Pathology, Washington University School of Medicine, St. Louis, Missouri
| | - Alexander R Pinto
- Baker Heart and Diabetes Research Institute, Melbourne, Australia; Centre for Cardiovascular Biology and Disease Research, La Trobe University, Melbourne, Australia
| | - Slava Epelman
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada; Ted Rogers Centre for Heart Research, Toronto, Ontario, Canada; University of Toronto, Department of Laboratory Medicine and Pathobiology, Toronto, Ontario, Canada; Department of Immunology, University of Toronto, Toronto, Ontario, Canada; Peter Munk Cardiac Centre, Toronto, Ontario, Canada
| | - Benjamin J Kopecky
- Division of Cardiovascular Medicine, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri; Center for Cardiovascular Research, Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri
| | - Xavier Clemente-Casares
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada; Department of Immunology, University of Toronto, Toronto, Ontario, Canada
| | - James Godwin
- The Jackson Laboratory, Bar Harbor, Maine; Mt. Desert Island Biological Laboratory, Bar Harbor, Maine
| | - Nadia Rosenthal
- The Jackson Laboratory, Bar Harbor, Maine; National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Jason C Kovacic
- Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
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14
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Błyszczuk P. Myocarditis in Humans and in Experimental Animal Models. Front Cardiovasc Med 2019; 6:64. [PMID: 31157241 PMCID: PMC6532015 DOI: 10.3389/fcvm.2019.00064] [Citation(s) in RCA: 106] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Accepted: 04/30/2019] [Indexed: 12/21/2022] Open
Abstract
Myocarditis is defined as an inflammation of the cardiac muscle. In humans, various infectious and non-infectious triggers induce myocarditis with a broad spectrum of histological presentations and clinical symptoms of the disease. Myocarditis often resolves spontaneously, but some patients develop heart failure and require organ transplantation. The need to understand cellular and molecular mechanisms of inflammatory heart diseases led to the development of mouse models for experimental myocarditis. It has been shown that pathogenic agents inducing myocarditis in humans can often trigger the disease in mice. Due to multiple etiologies of inflammatory heart diseases in humans, a number of different experimental approaches have been developed to induce myocarditis in mice. Accordingly, experimental myocarditis in mice can be induced by infection with cardiotropic agents, such as coxsackievirus B3 and protozoan parasite Trypanosoma cruzi or by activating autoimmune responses against heart-specific antigens. In certain models, myocarditis is followed by the phenotype of dilated cardiomyopathy and the end stage of heart failure. This review describes the most commonly used mouse models of experimental myocarditis with a focus on the role of the innate and adaptive immune systems in induction and progression of the disease. The review discusses also advantages and limitations of individual mouse models in the context of the clinical manifestation and the course of the disease in humans. Finally, animal-free alternatives in myocarditis research are outlined.
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Affiliation(s)
- Przemysław Błyszczuk
- Department of Clinical Immunology, Jagiellonian University Medical College, Cracow, Poland.,Department of Rheumatology, Center of Experimental Rheumatology, University Hospital Zurich, Zurich, Switzerland
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15
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Cardiovascular inflammation: RNA takes the lead. J Mol Cell Cardiol 2019; 129:247-256. [PMID: 30880251 DOI: 10.1016/j.yjmcc.2019.03.012] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Revised: 03/12/2019] [Accepted: 03/13/2019] [Indexed: 12/19/2022]
Abstract
Inflammation has recently gained tremendous attention as a key contributor in several chronic diseases. While physiological inflammation is essential to counter a wide variety of damaging stimuli and to improve wound healing, dysregulated inflammation such as in the myocardium and vasculature can promote cardiovascular diseases. Given the high severity, prevalence, and economic burden of these diseases, understanding the factors involved in the regulation of physiological inflammation is essential. Like other complex biological phenomena, RNA-based processes are emerging as major regulators of inflammatory responses. Among such processes are cis-regulatory elements in the mRNA of inflammatory genes, noncoding RNAs directing the production or localization of inflammatory cytokines/chemokines, or pathogenic RNA driving inflammatory responses. In this review, we describe several specific RNA-based molecular mechanisms by which physiological inflammation pertaining to cardiovascular diseases is regulated. These include the role of AU-rich element-containing mRNAs, long non-coding RNAs, microRNAs, and viral RNAs.
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16
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Bondue A, Arbustini E, Bianco A, Ciccarelli M, Dawson D, De Rosa M, Hamdani N, Hilfiker-Kleiner D, Meder B, Leite-Moreira AF, Thum T, Tocchetti CG, Varricchi G, Van der Velden J, Walsh R, Heymans S. Complex roads from genotype to phenotype in dilated cardiomyopathy: scientific update from the Working Group of Myocardial Function of the European Society of Cardiology. Cardiovasc Res 2018; 114:1287-1303. [PMID: 29800419 PMCID: PMC6054212 DOI: 10.1093/cvr/cvy122] [Citation(s) in RCA: 89] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Revised: 05/05/2018] [Accepted: 05/16/2018] [Indexed: 12/14/2022] Open
Abstract
Dilated cardiomyopathy (DCM) frequently affects relatively young, economically, and socially active adults, and is an important cause of heart failure and transplantation. DCM is a complex disease and its pathological architecture encounters many genetic determinants interacting with environmental factors. The old perspective that every pathogenic gene mutation would lead to a diseased heart, is now being replaced by the novel observation that the phenotype depends not only on the penetrance-malignancy of the mutated gene-but also on epigenetics, age, toxic factors, pregnancy, and a diversity of acquired diseases. This review discusses how gene mutations will result in mutation-specific molecular alterations in the heart including increased mitochondrial oxidation (sarcomeric gene e.g. TTN), decreased calcium sensitivity (sarcomeric genes), fibrosis (e.g. LMNA and TTN), or inflammation. Therefore, getting a complete picture of the DCM patient will include genomic data, molecular assessment by preference from cardiac samples, stratification according to co-morbidities, and phenotypic description. Those data will help to better guide the heart failure and anti-arrhythmic treatment, predict response to therapy, develop novel siRNA-based gene silencing for malignant gene mutations, or intervene with mutation-specific altered gene pathways in the heart.This article is part of the Mini Review Series from the Varenna 2017 meeting of the Working Group of Myocardial Function of the European Society of Cardiology.
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Affiliation(s)
- Antoine Bondue
- Department of Cardiology, CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium
| | - Eloisa Arbustini
- Centre for Inherited Cardiovascular Diseases, IRCCS Foundation, University Hospital Policlinico San Matteo, Pavia, Italy
| | - Anna Bianco
- Department of Translational Medical Sciences, Federico II University, Naples, Italy
- Department of Cardiology, Maastricht University Medical Center & CARIM, Maastricht University, Maastricht, The Netherlands
| | - Michele Ciccarelli
- School of Medicine, Surgery and Dentistry, University of Salerno, Salerno, Italy
| | - Dana Dawson
- School of Medicine and Dentistry, University of Aberdeen, Aberdeen, UK
| | - Matteo De Rosa
- School of Medicine, Surgery and Dentistry, University of Salerno, Salerno, Italy
| | - Nazha Hamdani
- Department of Systems Physiology, Ruhr University Bochum, Bochum, Germany
| | - Denise Hilfiker-Kleiner
- Molecular Cardiology, Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany
| | - Benjamin Meder
- Department of Cardiology, Heidelberg University, Heidelberg, Germany
- Department of Genetics, Stanford University School of Medicine, Genome Technology Center, Palo Alto, CA, USA
| | - Adelino F Leite-Moreira
- Cardiovascular R&D Unit, Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal
- Department of Cardiothoracic Surgery, Hospital of S. João, Porto, Portugal
| | - Thomas Thum
- Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Hannover, Germany
| | - Carlo G Tocchetti
- Department of Translational Medical Sciences, Federico II University, Naples, Italy
| | - Gilda Varricchi
- Department of Translational Medical Sciences, Federico II University, Naples, Italy
| | - Jolanda Van der Velden
- Department of Physiology, VU University Medical Centre, Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands
- Netherlands Heart Institute, Utrecht, The Netherlands
| | - Roddy Walsh
- Cardiovascular Research Center, Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, London, UK
| | - Stephane Heymans
- Department of Cardiology, Maastricht University Medical Center & CARIM, Maastricht University, Maastricht, The Netherlands
- Netherlands Heart Institute, Utrecht, The Netherlands
- Department of Cardiovascular Sciences, Leuven University, Leuven, Belgium
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17
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Becher PM, Hinrichs S, Fluschnik N, Hennigs JK, Klingel K, Blankenberg S, Westermann D, Lindner D. Role of Toll-like receptors and interferon regulatory factors in different experimental heart failure models of diverse etiology: IRF7 as novel cardiovascular stress-inducible factor. PLoS One 2018. [PMID: 29538462 PMCID: PMC5851607 DOI: 10.1371/journal.pone.0193844] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Heart failure (HF) is a leading cause of morbidity and mortality in the western world. Although optimal medical care and treatment is widely available, the prognosis of patients with HF is still poor. Toll-like receptors (TLRs) are important compartments of the innate immunity. Current studies have identified TLRs as critical mediators in cardiovascular diseases. In the present study, we investigated the involvement of TLRs and interferon (IFN) regulatory factors (IRFs) in different experimental HF models including viral myocarditis, myocardial ischemia, diabetes mellitus, and cardiac hypertrophy. In addition, we investigated for the first time comprehensive TLR and IRF gene and protein expression under basal conditions in murine and human cardiac tissue. We found that Tlr4, Tlr9 and Irf7 displayed highest gene expression under basal conditions, indicating their significant role in first-line defense in the murine and human heart. Moreover, induction of TLRs and IRFs clearly differs between the various experimental HF models of diverse etiology and the concomitant inflammatory status. In the HF model of acute viral-induced myocarditis, TLR and IRF activation displayed the uppermost gene expression in comparison to the remaining experimental HF models, indicating the highest amount of myocardial inflammation in myocarditis. In detail, Irf7 displayed by far the highest gene expression during acute viral infection. Interestingly, post myocardial infarction TLR and IRF gene expression was almost exclusively increased in the infarct zone after myocardial ischemia (Tlr2, Tlr3, Tlr6, Tlr7, Tlr9, Irf3, Irf7). With one exception, Irf3 showed a decreased gene expression in the remote zone post infarction. Finally, we identified Irf7 as novel cardiovascular stress-inducible factor in the pathologically stressed heart. These findings on TLR and IRF function in the inflamed heart highlight the complexity of inflammatory immune response and raise more interesting questions for future investigation.
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Affiliation(s)
- Peter Moritz Becher
- Department for General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany
- * E-mail:
| | - Svenja Hinrichs
- Department for General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany
- DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany
| | - Nina Fluschnik
- Department for General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany
| | - Jan K. Hennigs
- Section Pneumology, Department of Medicine II, University Medical Center Hamburg Eppendorf, Hamburg, Germany
| | - Karin Klingel
- Cardiopathology, Institute for Pathology and Neuropathology, Eberhard-Karls-University Tübingen, Tübingen, Germany
| | - Stefan Blankenberg
- Department for General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany
- DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany
| | - Dirk Westermann
- Department for General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany
- DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany
| | - Diana Lindner
- Department for General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany
- DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, Hamburg, Germany
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18
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Abstract
Heart diseases are major causes of mortality. Cardiac hypertrophy, myocardial infarction (MI), viral cardiomyopathy, ischemic and reperfusion (I/R) heart injury finally lead to heart failure and death. Insulin and IGF1 signal pathways play key roles in normal cardiomyocyte growth and physiological cardiac hypertrophy while inflammatory signal pathway is associated with pathological cardiac hypertrophy, MI, viral cardiomyopathy, I/R heart injury, and heart failure. Adapter proteins are the major family proteins, which transduce signals from insulin, IGF1, or cytokine receptors to the downstream pathways and have been shown to regulate variety of heart diseases. Here, we summarized the recent advances in understanding the physiological and pathological roles of adapter proteins in heart failure.
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Affiliation(s)
- Li Tao
- Cardiovascular Center, 305 Hospital of People's Liberation Army, Beijing, 100017, China
| | - Linna Jia
- Key Laboratory of Molecular Epigenetics of the Ministry of Education (MOE), School of Life Sciences, Northeast Normal University, Changchun, 130024, Jilin, China
| | - Yuntian Li
- Cardiovascular Center, 305 Hospital of People's Liberation Army, Beijing, 100017, China
| | - Chengyun Song
- Cardiovascular Center, 305 Hospital of People's Liberation Army, Beijing, 100017, China.
| | - Zheng Chen
- Key Laboratory of Molecular Epigenetics of the Ministry of Education (MOE), School of Life Sciences, Northeast Normal University, Changchun, 130024, Jilin, China.
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19
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Yu L, Feng Z. The Role of Toll-Like Receptor Signaling in the Progression of Heart Failure. Mediators Inflamm 2018; 2018:9874109. [PMID: 29576748 PMCID: PMC5822798 DOI: 10.1155/2018/9874109] [Citation(s) in RCA: 103] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2017] [Revised: 11/28/2017] [Accepted: 12/14/2017] [Indexed: 12/14/2022] Open
Abstract
Medical systems worldwide are being faced with a growing need to understand mechanisms behind the pathogenesis of heart failure (HF) that is considered as a leading cause of morbidity and mortality around the world. Elevated levels of inflammatory mediators have been identified in patients with HF, which are primarily manifestations of innate immune responses mediated by pattern recognition receptors (PRRs). Toll-like receptors (TLRs), which belong to PRRs, are subjected to the release of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) to generate innate immune responses. More and more emerging data indicate that TLR signaling pathway molecules are involved in the progression of HF. Herein, we present new data with regard to the activation of TLRs in the failing heart, focusing on TLR2, TLR3, TLR4, and TLR9, and suggest the potential use of TLRs in target therapy.
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Affiliation(s)
- Lili Yu
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan 453003, China
- Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA 70808, USA
- Henan Key Laboratory of immunology and Targeted Drugs, Xinxiang, Henan 453003, China
- Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, Xinxiang, Henan 453003, China
| | - Zhiwei Feng
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan 453003, China
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Frantz S, Falcao-Pires I, Balligand JL, Bauersachs J, Brutsaert D, Ciccarelli M, Dawson D, de Windt LJ, Giacca M, Hamdani N, Hilfiker-Kleiner D, Hirsch E, Leite-Moreira A, Mayr M, Thum T, Tocchetti CG, van der Velden J, Varricchi G, Heymans S. The innate immune system in chronic cardiomyopathy: a European Society of Cardiology (ESC) scientific statement from the Working Group on Myocardial Function of the ESC. Eur J Heart Fail 2018; 20:445-459. [PMID: 29333691 PMCID: PMC5993315 DOI: 10.1002/ejhf.1138] [Citation(s) in RCA: 129] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2017] [Revised: 12/03/2017] [Accepted: 12/18/2017] [Indexed: 12/11/2022] Open
Abstract
Activation of the immune system in heart failure (HF) has been recognized for over 20 years. Initially, experimental studies demonstrated a maladaptive role of the immune system. However, several phase III trials failed to show beneficial effects in HF with therapies directed against an immune activation. Preclinical studies today describe positive and negative effects of immune activation in HF. These different effects depend on timing and aetiology of HF. Therefore, herein we give a detailed review on immune mechanisms and their importance for the development of HF with a special focus on commonalities and differences between different forms of cardiomyopathies. The role of the immune system in ischaemic, hypertensive, diabetic, toxic, viral, genetic, peripartum, and autoimmune cardiomyopathy is discussed in depth. Overall, initial damage to the heart leads to disease specific activation of the immune system whereas in the chronic phase of HF overlapping mechanisms occur in different aetiologies.
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Affiliation(s)
- Stefan Frantz
- Department of Internal Medicine I, University Hospital Würzburg, Germany; Department of Internal Medicine III, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Ines Falcao-Pires
- Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Jean-Luc Balligand
- Pole of Pharmacology and Therapeutics, Institut de Recherche Experimentale et Clinique (IREC), and Clinique Universitaire Saint-Luc, Université Catholique de Louvain, Brussels, Belgium
| | - Johann Bauersachs
- Department of Cardiology and Angiology, Medizinische Hochschule, Hannover, Germany
| | | | - Michele Ciccarelli
- Department of Medicine and Surgery, University of Salerno, Baronissi, Italy
| | - Dana Dawson
- School of Medicine and Dentistry, University of Aberdeen, Aberdeen, Scotland
| | - Leon J de Windt
- Department of Cardiology, CARIM School for Cardiovascular Diseases Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands
| | - Mauro Giacca
- International Centre for Genetic Engineering and Biotechnology (ICGEB) and Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy
| | - Nazha Hamdani
- Department of Cardiovascular Physiology, Ruhr University Bochum, Bochum, Germany
| | - Denise Hilfiker-Kleiner
- Molecular Cardiology, Department of Cardiology and Angiology, Medizinische Hochschule, Hannover, Germany
| | - Emilio Hirsch
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
| | - Adelino Leite-Moreira
- Department of Physiology and Cardiothoracic Surgery and Cardiovascular Research Centre, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Manuel Mayr
- The James Black Centre and King's British Heart Foundation Centre, King's College, University of London, London, UK
| | - Thomas Thum
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), IFB-Tx, and REBIRTH Excellence Cluster, Hannover Medical School, Hannover, Germany
| | - Carlo G Tocchetti
- Department of Translational Medical Sciences, Federico II University, Naples, Italy
| | - Jolanda van der Velden
- Department of Physiology, VU University Medical Center, Amsterdam Cardiovascular Sciences Institute, Amsterdam, The Netherlands.,Netherlands Heart Institute, Utrecht, The Netherlands
| | - Gilda Varricchi
- Department of Translational Medical Sciences, Federico II University, Naples, Italy.,Center for Basic and Clinical Immunology Research (CISI), Federico II University, Naples, Italy
| | - Stephane Heymans
- Department of Cardiology, CARIM School for Cardiovascular Diseases Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands.,Netherlands Heart Institute, Utrecht, The Netherlands.,Department of Cardiovascular Sciences, Leuven University, Leuven, Belgium
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Müller I, Vogl T, Pappritz K, Miteva K, Savvatis K, Rohde D, Most P, Lassner D, Pieske B, Kühl U, Van Linthout S, Tschöpe C. Pathogenic Role of the Damage-Associated Molecular Patterns S100A8 and S100A9 in Coxsackievirus B3-Induced Myocarditis. Circ Heart Fail 2017; 10:CIRCHEARTFAILURE.117.004125. [PMID: 29158436 DOI: 10.1161/circheartfailure.117.004125] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2017] [Accepted: 10/23/2017] [Indexed: 01/10/2023]
Abstract
BACKGROUND The alarmins S100A8 and S100A9 are damage-associated molecular patterns, which play a pivotal role in cardiovascular diseases, inflammation, and viral infections. We aimed to investigate their role in Coxsackievirus B3 (CVB3)-induced myocarditis. METHODS AND RESULTS S100A8 and S100A9 mRNA expression was 13.0-fold (P=0.012) and 5.1-fold (P=0.038) higher in endomyocardial biopsies from patients with CVB3-positive myocarditis compared with controls, respectively. Elimination of CVB3 led to a downregulation of these alarmins. CVB3-infected mice developed an impaired left ventricular function and displayed an increased left ventricular S100A8 and S100A9 protein expression versus controls. In contrast, CVB3-infected S100A9 knockout mice, which are also a complete knockout for S100A8 on protein level, showed an improved left ventricular function, which was associated with a reduced cardiac inflammatory and oxidative response, and lower CVB3 copy number compared with wild-type CVB3 mice. Exogenous application of S100A8 to S100A9 knockout CVB3 mice induced a severe myocarditis similar to wild-type CVB3 mice. In CVB3-infected HL-1 cells, S100A8 and S100A9 enhanced oxidative stress and CVB3 copy number compared with unstimulated infected cells. In CVB3-infected RAW macrophages, both alarmins increased MIP-2 (macrophage inflammatory protein-2) chemokine expression, which was reduced in CVB3 S100A8 knockdown versus scrambled siRNA CVB3 cells. CONCLUSIONS S100A8 and S100A9 aggravate CVB3-induced myocarditis and might serve as therapeutic targets in inflammatory cardiomyopathies.
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Affiliation(s)
- Irene Müller
- From the Department of Cardiology and Pneumology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Germany (I.M., K.P., K.M., B.P., U.K., S.V.L., C.T., K.S.); Berlin-Brandenburg Center for Regenerative Therapies, Charité, University Medicine Berlin, Campus Virchow, Germany (I.M., K.P., K.M., K.S., S.V.L., C.T.); DZHK (German Center for Cardiovascular Research), Partner Site Berlin (I.M., K.P., B.P., S.V.L., C.T.); Department of Immunology, University of Münster, Germany (T.V.); Inherited Cardiovascular Diseases Unit, Barts Health NHS Trust, Barts Heart Centre, London, United Kingdom (K.S.); William Harvey Research Institute, Queen Mary University London, United Kingdom (K.S.); Department of Internal Medicine III, Center for Molecular and Translational Cardiology, University of Heidelberg, Germany (D.R., P.M.); DZHK, (German Center for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany (P.M.); Institut Kardiale Diagnostik und Therapie (IKDT), Berlin, Germany (D.L.); and Department of Cardiology, Deutsches Herzzentrum Berlin (DHZB), Germany (B.P.)
| | - Thomas Vogl
- From the Department of Cardiology and Pneumology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Germany (I.M., K.P., K.M., B.P., U.K., S.V.L., C.T., K.S.); Berlin-Brandenburg Center for Regenerative Therapies, Charité, University Medicine Berlin, Campus Virchow, Germany (I.M., K.P., K.M., K.S., S.V.L., C.T.); DZHK (German Center for Cardiovascular Research), Partner Site Berlin (I.M., K.P., B.P., S.V.L., C.T.); Department of Immunology, University of Münster, Germany (T.V.); Inherited Cardiovascular Diseases Unit, Barts Health NHS Trust, Barts Heart Centre, London, United Kingdom (K.S.); William Harvey Research Institute, Queen Mary University London, United Kingdom (K.S.); Department of Internal Medicine III, Center for Molecular and Translational Cardiology, University of Heidelberg, Germany (D.R., P.M.); DZHK, (German Center for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany (P.M.); Institut Kardiale Diagnostik und Therapie (IKDT), Berlin, Germany (D.L.); and Department of Cardiology, Deutsches Herzzentrum Berlin (DHZB), Germany (B.P.)
| | - Kathleen Pappritz
- From the Department of Cardiology and Pneumology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Germany (I.M., K.P., K.M., B.P., U.K., S.V.L., C.T., K.S.); Berlin-Brandenburg Center for Regenerative Therapies, Charité, University Medicine Berlin, Campus Virchow, Germany (I.M., K.P., K.M., K.S., S.V.L., C.T.); DZHK (German Center for Cardiovascular Research), Partner Site Berlin (I.M., K.P., B.P., S.V.L., C.T.); Department of Immunology, University of Münster, Germany (T.V.); Inherited Cardiovascular Diseases Unit, Barts Health NHS Trust, Barts Heart Centre, London, United Kingdom (K.S.); William Harvey Research Institute, Queen Mary University London, United Kingdom (K.S.); Department of Internal Medicine III, Center for Molecular and Translational Cardiology, University of Heidelberg, Germany (D.R., P.M.); DZHK, (German Center for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany (P.M.); Institut Kardiale Diagnostik und Therapie (IKDT), Berlin, Germany (D.L.); and Department of Cardiology, Deutsches Herzzentrum Berlin (DHZB), Germany (B.P.)
| | - Kapka Miteva
- From the Department of Cardiology and Pneumology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Germany (I.M., K.P., K.M., B.P., U.K., S.V.L., C.T., K.S.); Berlin-Brandenburg Center for Regenerative Therapies, Charité, University Medicine Berlin, Campus Virchow, Germany (I.M., K.P., K.M., K.S., S.V.L., C.T.); DZHK (German Center for Cardiovascular Research), Partner Site Berlin (I.M., K.P., B.P., S.V.L., C.T.); Department of Immunology, University of Münster, Germany (T.V.); Inherited Cardiovascular Diseases Unit, Barts Health NHS Trust, Barts Heart Centre, London, United Kingdom (K.S.); William Harvey Research Institute, Queen Mary University London, United Kingdom (K.S.); Department of Internal Medicine III, Center for Molecular and Translational Cardiology, University of Heidelberg, Germany (D.R., P.M.); DZHK, (German Center for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany (P.M.); Institut Kardiale Diagnostik und Therapie (IKDT), Berlin, Germany (D.L.); and Department of Cardiology, Deutsches Herzzentrum Berlin (DHZB), Germany (B.P.)
| | - Konstantinos Savvatis
- From the Department of Cardiology and Pneumology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Germany (I.M., K.P., K.M., B.P., U.K., S.V.L., C.T., K.S.); Berlin-Brandenburg Center for Regenerative Therapies, Charité, University Medicine Berlin, Campus Virchow, Germany (I.M., K.P., K.M., K.S., S.V.L., C.T.); DZHK (German Center for Cardiovascular Research), Partner Site Berlin (I.M., K.P., B.P., S.V.L., C.T.); Department of Immunology, University of Münster, Germany (T.V.); Inherited Cardiovascular Diseases Unit, Barts Health NHS Trust, Barts Heart Centre, London, United Kingdom (K.S.); William Harvey Research Institute, Queen Mary University London, United Kingdom (K.S.); Department of Internal Medicine III, Center for Molecular and Translational Cardiology, University of Heidelberg, Germany (D.R., P.M.); DZHK, (German Center for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany (P.M.); Institut Kardiale Diagnostik und Therapie (IKDT), Berlin, Germany (D.L.); and Department of Cardiology, Deutsches Herzzentrum Berlin (DHZB), Germany (B.P.)
| | - David Rohde
- From the Department of Cardiology and Pneumology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Germany (I.M., K.P., K.M., B.P., U.K., S.V.L., C.T., K.S.); Berlin-Brandenburg Center for Regenerative Therapies, Charité, University Medicine Berlin, Campus Virchow, Germany (I.M., K.P., K.M., K.S., S.V.L., C.T.); DZHK (German Center for Cardiovascular Research), Partner Site Berlin (I.M., K.P., B.P., S.V.L., C.T.); Department of Immunology, University of Münster, Germany (T.V.); Inherited Cardiovascular Diseases Unit, Barts Health NHS Trust, Barts Heart Centre, London, United Kingdom (K.S.); William Harvey Research Institute, Queen Mary University London, United Kingdom (K.S.); Department of Internal Medicine III, Center for Molecular and Translational Cardiology, University of Heidelberg, Germany (D.R., P.M.); DZHK, (German Center for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany (P.M.); Institut Kardiale Diagnostik und Therapie (IKDT), Berlin, Germany (D.L.); and Department of Cardiology, Deutsches Herzzentrum Berlin (DHZB), Germany (B.P.)
| | - Patrick Most
- From the Department of Cardiology and Pneumology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Germany (I.M., K.P., K.M., B.P., U.K., S.V.L., C.T., K.S.); Berlin-Brandenburg Center for Regenerative Therapies, Charité, University Medicine Berlin, Campus Virchow, Germany (I.M., K.P., K.M., K.S., S.V.L., C.T.); DZHK (German Center for Cardiovascular Research), Partner Site Berlin (I.M., K.P., B.P., S.V.L., C.T.); Department of Immunology, University of Münster, Germany (T.V.); Inherited Cardiovascular Diseases Unit, Barts Health NHS Trust, Barts Heart Centre, London, United Kingdom (K.S.); William Harvey Research Institute, Queen Mary University London, United Kingdom (K.S.); Department of Internal Medicine III, Center for Molecular and Translational Cardiology, University of Heidelberg, Germany (D.R., P.M.); DZHK, (German Center for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany (P.M.); Institut Kardiale Diagnostik und Therapie (IKDT), Berlin, Germany (D.L.); and Department of Cardiology, Deutsches Herzzentrum Berlin (DHZB), Germany (B.P.)
| | - Dirk Lassner
- From the Department of Cardiology and Pneumology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Germany (I.M., K.P., K.M., B.P., U.K., S.V.L., C.T., K.S.); Berlin-Brandenburg Center for Regenerative Therapies, Charité, University Medicine Berlin, Campus Virchow, Germany (I.M., K.P., K.M., K.S., S.V.L., C.T.); DZHK (German Center for Cardiovascular Research), Partner Site Berlin (I.M., K.P., B.P., S.V.L., C.T.); Department of Immunology, University of Münster, Germany (T.V.); Inherited Cardiovascular Diseases Unit, Barts Health NHS Trust, Barts Heart Centre, London, United Kingdom (K.S.); William Harvey Research Institute, Queen Mary University London, United Kingdom (K.S.); Department of Internal Medicine III, Center for Molecular and Translational Cardiology, University of Heidelberg, Germany (D.R., P.M.); DZHK, (German Center for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany (P.M.); Institut Kardiale Diagnostik und Therapie (IKDT), Berlin, Germany (D.L.); and Department of Cardiology, Deutsches Herzzentrum Berlin (DHZB), Germany (B.P.)
| | - Burkert Pieske
- From the Department of Cardiology and Pneumology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Germany (I.M., K.P., K.M., B.P., U.K., S.V.L., C.T., K.S.); Berlin-Brandenburg Center for Regenerative Therapies, Charité, University Medicine Berlin, Campus Virchow, Germany (I.M., K.P., K.M., K.S., S.V.L., C.T.); DZHK (German Center for Cardiovascular Research), Partner Site Berlin (I.M., K.P., B.P., S.V.L., C.T.); Department of Immunology, University of Münster, Germany (T.V.); Inherited Cardiovascular Diseases Unit, Barts Health NHS Trust, Barts Heart Centre, London, United Kingdom (K.S.); William Harvey Research Institute, Queen Mary University London, United Kingdom (K.S.); Department of Internal Medicine III, Center for Molecular and Translational Cardiology, University of Heidelberg, Germany (D.R., P.M.); DZHK, (German Center for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany (P.M.); Institut Kardiale Diagnostik und Therapie (IKDT), Berlin, Germany (D.L.); and Department of Cardiology, Deutsches Herzzentrum Berlin (DHZB), Germany (B.P.)
| | - Uwe Kühl
- From the Department of Cardiology and Pneumology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Germany (I.M., K.P., K.M., B.P., U.K., S.V.L., C.T., K.S.); Berlin-Brandenburg Center for Regenerative Therapies, Charité, University Medicine Berlin, Campus Virchow, Germany (I.M., K.P., K.M., K.S., S.V.L., C.T.); DZHK (German Center for Cardiovascular Research), Partner Site Berlin (I.M., K.P., B.P., S.V.L., C.T.); Department of Immunology, University of Münster, Germany (T.V.); Inherited Cardiovascular Diseases Unit, Barts Health NHS Trust, Barts Heart Centre, London, United Kingdom (K.S.); William Harvey Research Institute, Queen Mary University London, United Kingdom (K.S.); Department of Internal Medicine III, Center for Molecular and Translational Cardiology, University of Heidelberg, Germany (D.R., P.M.); DZHK, (German Center for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany (P.M.); Institut Kardiale Diagnostik und Therapie (IKDT), Berlin, Germany (D.L.); and Department of Cardiology, Deutsches Herzzentrum Berlin (DHZB), Germany (B.P.)
| | - Sophie Van Linthout
- From the Department of Cardiology and Pneumology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Germany (I.M., K.P., K.M., B.P., U.K., S.V.L., C.T., K.S.); Berlin-Brandenburg Center for Regenerative Therapies, Charité, University Medicine Berlin, Campus Virchow, Germany (I.M., K.P., K.M., K.S., S.V.L., C.T.); DZHK (German Center for Cardiovascular Research), Partner Site Berlin (I.M., K.P., B.P., S.V.L., C.T.); Department of Immunology, University of Münster, Germany (T.V.); Inherited Cardiovascular Diseases Unit, Barts Health NHS Trust, Barts Heart Centre, London, United Kingdom (K.S.); William Harvey Research Institute, Queen Mary University London, United Kingdom (K.S.); Department of Internal Medicine III, Center for Molecular and Translational Cardiology, University of Heidelberg, Germany (D.R., P.M.); DZHK, (German Center for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany (P.M.); Institut Kardiale Diagnostik und Therapie (IKDT), Berlin, Germany (D.L.); and Department of Cardiology, Deutsches Herzzentrum Berlin (DHZB), Germany (B.P.)
| | - Carsten Tschöpe
- From the Department of Cardiology and Pneumology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Germany (I.M., K.P., K.M., B.P., U.K., S.V.L., C.T., K.S.); Berlin-Brandenburg Center for Regenerative Therapies, Charité, University Medicine Berlin, Campus Virchow, Germany (I.M., K.P., K.M., K.S., S.V.L., C.T.); DZHK (German Center for Cardiovascular Research), Partner Site Berlin (I.M., K.P., B.P., S.V.L., C.T.); Department of Immunology, University of Münster, Germany (T.V.); Inherited Cardiovascular Diseases Unit, Barts Health NHS Trust, Barts Heart Centre, London, United Kingdom (K.S.); William Harvey Research Institute, Queen Mary University London, United Kingdom (K.S.); Department of Internal Medicine III, Center for Molecular and Translational Cardiology, University of Heidelberg, Germany (D.R., P.M.); DZHK, (German Center for Cardiovascular Research), partner site Heidelberg/Mannheim, Germany (P.M.); Institut Kardiale Diagnostik und Therapie (IKDT), Berlin, Germany (D.L.); and Department of Cardiology, Deutsches Herzzentrum Berlin (DHZB), Germany (B.P.).
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Wei J, Zhang X, Zang S, Qin Q. Expression and functional characterization of TRIF in orange-spotted grouper (Epinephelus coioides). FISH & SHELLFISH IMMUNOLOGY 2017; 71:295-304. [PMID: 28964858 DOI: 10.1016/j.fsi.2017.09.063] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Revised: 09/15/2017] [Accepted: 09/26/2017] [Indexed: 06/07/2023]
Abstract
Antiviral immune responses are triggered by the innate immune recognition of viral infection. Toll/interleukin-1 receptor (TIR) domain containing adapter inducing interferon-β (TRIF) is an adapter in responding to activation of Toll-like receptors, which provides early clearance of viral pathogens. Our study focuses on the functional characterization of grouper TRIF (EcTRIF) based on the comparison of its sequence and functional evolution from grouper fish to mammals. The results show that the open reading frame of EcTRIF encoded a protein of 580 amino acids. Real-time PCR analysis indicates that EcTRIF was constitutively expressed in all the analyzed tissues in healthy grouper. EcTRIF was significantly induced in spleen post-LPS and poly (I:C) stimulation. Fluorescence microscopy shows that EcTRIF is colocalized with a Golgi apparatus marker, implying its unique subcellular localization in the Golgi apparatus. Luciferase reporter assays confirmed that EcTRIF was able to activate the IFN and NF-κB promoter. Overexpression of EcTRIF in grouper brain cells inhibited the replication of red-spotted grouper nervous necrosis virus (RGNNV). These results indicate that EcTRIF plays an important role in modulating antiviral innate immune responses. Our results have applications in functional studies on TRIF in teleost fish and immune evolution.
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Affiliation(s)
- Jingguang Wei
- College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, PR China
| | - Xin Zhang
- College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, PR China
| | - Shaoqing Zang
- Key Laboratory of Tropical Marine Bio-resources and Ecology, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou, 510301, PR China; University of Chinese Academy of Sciences, Beijing, 100049, PR China; Guangdong Provincial Key Laboratory of Applied Marine Biology, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou, 510301, PR China
| | - Qiwei Qin
- College of Marine Sciences, South China Agricultural University, Guangzhou, 510642, PR China; Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266000, PR China.
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Immunological and pathological consequences of coxsackievirus RNA persistence in the heart. Virology 2017; 512:104-112. [PMID: 28950225 DOI: 10.1016/j.virol.2017.09.017] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2017] [Revised: 09/14/2017] [Accepted: 09/18/2017] [Indexed: 12/14/2022]
Abstract
Type B coxsackieviruses (CVB) can cause myocarditis and dilated cardiomyopathy (DCM), a potentially-fatal sequela that has been correlated to the persistence of viral RNA. Herein, we demonstrate that cardiac RNA persistence can be established even after an inapparent primary infection. Using an inducible Cre/lox mouse model, we ask: (i) Does persistent CVB3 RNA cause ongoing immune activation? (ii) If T1IFN signaling into cardiomyocytes is ablated after RNA persistence is established, is there any change in the abundance of persistent CVB3 RNA and/or does cytopathic infectious virus re-emerge? (iii) Does this loss of T1IFN responsiveness by cardiomyocytes lead to the recurrence/exacerbation of myocarditis? Our findings suggest that persistent enteroviral RNAs probably do not contribute to ongoing myocardial disease, and are more likely to be the fading remnants of a recent, possibly sub-clinical, primary infection which may have set in motion the process that ultimately ends in DCM.
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Sesti-Costa R, Françozo MCS, Silva GK, Proenca-Modena JL, Silva JS. TLR3 is required for survival following Coxsackievirus B3 infection by driving T lymphocyte activation and polarization: The role of dendritic cells. PLoS One 2017; 12:e0185819. [PMID: 28973047 PMCID: PMC5626506 DOI: 10.1371/journal.pone.0185819] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2016] [Accepted: 09/20/2017] [Indexed: 11/21/2022] Open
Abstract
Type B coxsackievirus (CVB) is a common cause of acute and chronic myocarditis, meningitis and pancreatitis, often leading to heart failure and pancreatic deficiency. The polarization of CD4+ T lymphocytes and their cytokine milieu are key factors in the outcome of CVB-induced diseases. Thus, sensing the virus and driving the adaptive immune response are essential for the establishment of a protective immune response. TLR3 is a crucial virus recognition receptor that confers the host with resistance to CVB infection. In the current study, we found that TLR3 expression in dendritic cells plays a role in their activation upon CVB3 infection in vitro, as TLR3-deficient dendritic cells up-regulate CD80 and CD86 to a less degree than WT cells. Instead, they up-regulated the inhibitory molecule PD-L1 and secreted considerably lower levels of TNF-α and IL-10 and a higher level of IL-23. T lymphocyte proliferation in co-culture with CVB3-infected dendritic cells was increased by TLR3-expressing DCs and other cells. Furthermore, in the absence of TLR3, the T lymphocyte response was shifted toward a Th17 profile, which was previously reported to be deleterious for the host. TLR3-deficient mice were very susceptible to CVB3 infection, with increased pancreatic injury and extensive inflammatory infiltrate in the heart that was associated with uncontrolled viral replication. Adoptive transfer of TLR3+ dendritic cells slightly improved the survival of TLR-deficient mice following CVB3 infection. Therefore, our findings highlight the importance of TLR3 signaling in DCs and in other cells to induce activation and polarization of the CD4+ T lymphocyte response toward a Th1 profile and consequently for a better outcome of CVB3 infection. These data provide new insight into the immune-mediated mechanisms by which CVBs are recognized and cleared in order to prevent the development of myocarditis and pancreatitis and may contribute to the design of therapies for enteroviral infections.
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Affiliation(s)
- Renata Sesti-Costa
- Department of Biochemistry and Immunology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Marcela Cristina Santiago Françozo
- Department of Biochemistry and Immunology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil
- Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research GmbH, Hannover, Germany
| | - Grace Kelly Silva
- Department of Biochemistry and Immunology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - José Luiz Proenca-Modena
- Department of Genetics, Evolution and Bioagents, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil
| | - João Santana Silva
- Department of Biochemistry and Immunology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil
- * E-mail:
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Tschöpe C, Müller I, Xia Y, Savvatis K, Pappritz K, Pinkert S, Lassner D, Heimesaat MM, Spillmann F, Miteva K, Bereswill S, Schultheiss HP, Fechner H, Pieske B, Kühl U, Van Linthout S. NOD2 (Nucleotide-Binding Oligomerization Domain 2) Is a Major Pathogenic Mediator of Coxsackievirus B3-Induced Myocarditis. Circ Heart Fail 2017; 10:CIRCHEARTFAILURE.117.003870. [PMID: 28912259 DOI: 10.1161/circheartfailure.117.003870] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2017] [Accepted: 08/07/2017] [Indexed: 12/22/2022]
Abstract
BACKGROUND The cytoplasmatic pattern recognition receptor, NOD2 (nucleotide-binding oligomerization domain 2), belongs to the innate immune system and is among others responsible for the recognition of single-stranded RNA. With Coxsackievirus B3 (CVB3) being a single-stranded RNA virus, and the recent evidence that the NOD2 target, NLRP3 (NOD-like receptor family, pyrin domain containing 3) is of importance in the pathogenesis of CVB3-induced myocarditis, we aimed to unravel the role of NOD2 in CVB3-induced myocarditis. METHODS AND RESULTS Endomyocardial biopsy NOD2 mRNA expression was higher in CVB3-positive patients compared with patients with myocarditis but without evidence of persistent CVB3 infection. Left ventricular NOD2 mRNA expression was also induced in CVB3-induced myocarditis versus healthy control mice. NOD2 knockdown(-/-) mice were rescued from the detrimental CVB3-mediated effects as shown by a reduced cardiac inflammation (less cardiac infiltrates and suppression of proinflammatory cytokines), cardiac fibrosis, apoptosis, lower CAR (Coxsackievirus and adenovirus receptor) expression and CVB3 copy number, and an improved left ventricular function in NOD2-/- CVB3 mice compared with wild-type CVB3 mice. In agreement, NOD2-/- decreased the CVB3-induced inflammatory response, CVB3 copy number, and apoptosis in vitro. NOD2-/- was further associated with a reduction in CVB3-induced NLRP3 expression and activity as evidenced by lower ASC (apoptosis-associated speck-like protein containing a CARD) expression, caspase 1 activity, or IL-1β (interleukin-1β) protein expression under in vivo and in vitro CVB3 conditions. CONCLUSIONS NOD2 is an important mediator in the viral uptake and inflammatory response during the pathogenesis of CVB3 myocarditis.
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Affiliation(s)
- Carsten Tschöpe
- From the Department of Cardiology and Pneumology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Germany (C.T., Y.X., K.S., F.S., B.P., U.K., S.V.L.); DZHK (German Center for Cardiovascular Research), partner site Berlin, Germany (C.T., I.M., K.P., B.P., S.V.L.); Berlin-Brandenburg Center for Regenerative Therapies, Charité, University Medicine Berlin, Campus Virchow, Germany (C.T., I.M., K.P., K.M., S.V.L.); Department of Applied Biochemistry, Institute of Biotechnology, Technische Universität Berlin, Germany (S.P., H.F.); Institut Kardiale Diagnostik und Therapie (IKDT), Berlin, Germany (D.L., H.-P.S.); Institut für Mikrobiologie und Infektionsmedizin, Campus Benjamin Franklin, Berlin, Germany (M.M.H., S.B.); and Department of Cardiology, Deutsches Herzzentrum Berlin (DHZB), Germany (B.P.).
| | - Irene Müller
- From the Department of Cardiology and Pneumology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Germany (C.T., Y.X., K.S., F.S., B.P., U.K., S.V.L.); DZHK (German Center for Cardiovascular Research), partner site Berlin, Germany (C.T., I.M., K.P., B.P., S.V.L.); Berlin-Brandenburg Center for Regenerative Therapies, Charité, University Medicine Berlin, Campus Virchow, Germany (C.T., I.M., K.P., K.M., S.V.L.); Department of Applied Biochemistry, Institute of Biotechnology, Technische Universität Berlin, Germany (S.P., H.F.); Institut Kardiale Diagnostik und Therapie (IKDT), Berlin, Germany (D.L., H.-P.S.); Institut für Mikrobiologie und Infektionsmedizin, Campus Benjamin Franklin, Berlin, Germany (M.M.H., S.B.); and Department of Cardiology, Deutsches Herzzentrum Berlin (DHZB), Germany (B.P.)
| | - Yu Xia
- From the Department of Cardiology and Pneumology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Germany (C.T., Y.X., K.S., F.S., B.P., U.K., S.V.L.); DZHK (German Center for Cardiovascular Research), partner site Berlin, Germany (C.T., I.M., K.P., B.P., S.V.L.); Berlin-Brandenburg Center for Regenerative Therapies, Charité, University Medicine Berlin, Campus Virchow, Germany (C.T., I.M., K.P., K.M., S.V.L.); Department of Applied Biochemistry, Institute of Biotechnology, Technische Universität Berlin, Germany (S.P., H.F.); Institut Kardiale Diagnostik und Therapie (IKDT), Berlin, Germany (D.L., H.-P.S.); Institut für Mikrobiologie und Infektionsmedizin, Campus Benjamin Franklin, Berlin, Germany (M.M.H., S.B.); and Department of Cardiology, Deutsches Herzzentrum Berlin (DHZB), Germany (B.P.)
| | - Konstantinos Savvatis
- From the Department of Cardiology and Pneumology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Germany (C.T., Y.X., K.S., F.S., B.P., U.K., S.V.L.); DZHK (German Center for Cardiovascular Research), partner site Berlin, Germany (C.T., I.M., K.P., B.P., S.V.L.); Berlin-Brandenburg Center for Regenerative Therapies, Charité, University Medicine Berlin, Campus Virchow, Germany (C.T., I.M., K.P., K.M., S.V.L.); Department of Applied Biochemistry, Institute of Biotechnology, Technische Universität Berlin, Germany (S.P., H.F.); Institut Kardiale Diagnostik und Therapie (IKDT), Berlin, Germany (D.L., H.-P.S.); Institut für Mikrobiologie und Infektionsmedizin, Campus Benjamin Franklin, Berlin, Germany (M.M.H., S.B.); and Department of Cardiology, Deutsches Herzzentrum Berlin (DHZB), Germany (B.P.)
| | - Kathleen Pappritz
- From the Department of Cardiology and Pneumology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Germany (C.T., Y.X., K.S., F.S., B.P., U.K., S.V.L.); DZHK (German Center for Cardiovascular Research), partner site Berlin, Germany (C.T., I.M., K.P., B.P., S.V.L.); Berlin-Brandenburg Center for Regenerative Therapies, Charité, University Medicine Berlin, Campus Virchow, Germany (C.T., I.M., K.P., K.M., S.V.L.); Department of Applied Biochemistry, Institute of Biotechnology, Technische Universität Berlin, Germany (S.P., H.F.); Institut Kardiale Diagnostik und Therapie (IKDT), Berlin, Germany (D.L., H.-P.S.); Institut für Mikrobiologie und Infektionsmedizin, Campus Benjamin Franklin, Berlin, Germany (M.M.H., S.B.); and Department of Cardiology, Deutsches Herzzentrum Berlin (DHZB), Germany (B.P.)
| | - Sandra Pinkert
- From the Department of Cardiology and Pneumology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Germany (C.T., Y.X., K.S., F.S., B.P., U.K., S.V.L.); DZHK (German Center for Cardiovascular Research), partner site Berlin, Germany (C.T., I.M., K.P., B.P., S.V.L.); Berlin-Brandenburg Center for Regenerative Therapies, Charité, University Medicine Berlin, Campus Virchow, Germany (C.T., I.M., K.P., K.M., S.V.L.); Department of Applied Biochemistry, Institute of Biotechnology, Technische Universität Berlin, Germany (S.P., H.F.); Institut Kardiale Diagnostik und Therapie (IKDT), Berlin, Germany (D.L., H.-P.S.); Institut für Mikrobiologie und Infektionsmedizin, Campus Benjamin Franklin, Berlin, Germany (M.M.H., S.B.); and Department of Cardiology, Deutsches Herzzentrum Berlin (DHZB), Germany (B.P.)
| | - Dirk Lassner
- From the Department of Cardiology and Pneumology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Germany (C.T., Y.X., K.S., F.S., B.P., U.K., S.V.L.); DZHK (German Center for Cardiovascular Research), partner site Berlin, Germany (C.T., I.M., K.P., B.P., S.V.L.); Berlin-Brandenburg Center for Regenerative Therapies, Charité, University Medicine Berlin, Campus Virchow, Germany (C.T., I.M., K.P., K.M., S.V.L.); Department of Applied Biochemistry, Institute of Biotechnology, Technische Universität Berlin, Germany (S.P., H.F.); Institut Kardiale Diagnostik und Therapie (IKDT), Berlin, Germany (D.L., H.-P.S.); Institut für Mikrobiologie und Infektionsmedizin, Campus Benjamin Franklin, Berlin, Germany (M.M.H., S.B.); and Department of Cardiology, Deutsches Herzzentrum Berlin (DHZB), Germany (B.P.)
| | - Markus M Heimesaat
- From the Department of Cardiology and Pneumology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Germany (C.T., Y.X., K.S., F.S., B.P., U.K., S.V.L.); DZHK (German Center for Cardiovascular Research), partner site Berlin, Germany (C.T., I.M., K.P., B.P., S.V.L.); Berlin-Brandenburg Center for Regenerative Therapies, Charité, University Medicine Berlin, Campus Virchow, Germany (C.T., I.M., K.P., K.M., S.V.L.); Department of Applied Biochemistry, Institute of Biotechnology, Technische Universität Berlin, Germany (S.P., H.F.); Institut Kardiale Diagnostik und Therapie (IKDT), Berlin, Germany (D.L., H.-P.S.); Institut für Mikrobiologie und Infektionsmedizin, Campus Benjamin Franklin, Berlin, Germany (M.M.H., S.B.); and Department of Cardiology, Deutsches Herzzentrum Berlin (DHZB), Germany (B.P.)
| | - Frank Spillmann
- From the Department of Cardiology and Pneumology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Germany (C.T., Y.X., K.S., F.S., B.P., U.K., S.V.L.); DZHK (German Center for Cardiovascular Research), partner site Berlin, Germany (C.T., I.M., K.P., B.P., S.V.L.); Berlin-Brandenburg Center for Regenerative Therapies, Charité, University Medicine Berlin, Campus Virchow, Germany (C.T., I.M., K.P., K.M., S.V.L.); Department of Applied Biochemistry, Institute of Biotechnology, Technische Universität Berlin, Germany (S.P., H.F.); Institut Kardiale Diagnostik und Therapie (IKDT), Berlin, Germany (D.L., H.-P.S.); Institut für Mikrobiologie und Infektionsmedizin, Campus Benjamin Franklin, Berlin, Germany (M.M.H., S.B.); and Department of Cardiology, Deutsches Herzzentrum Berlin (DHZB), Germany (B.P.)
| | - Kapka Miteva
- From the Department of Cardiology and Pneumology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Germany (C.T., Y.X., K.S., F.S., B.P., U.K., S.V.L.); DZHK (German Center for Cardiovascular Research), partner site Berlin, Germany (C.T., I.M., K.P., B.P., S.V.L.); Berlin-Brandenburg Center for Regenerative Therapies, Charité, University Medicine Berlin, Campus Virchow, Germany (C.T., I.M., K.P., K.M., S.V.L.); Department of Applied Biochemistry, Institute of Biotechnology, Technische Universität Berlin, Germany (S.P., H.F.); Institut Kardiale Diagnostik und Therapie (IKDT), Berlin, Germany (D.L., H.-P.S.); Institut für Mikrobiologie und Infektionsmedizin, Campus Benjamin Franklin, Berlin, Germany (M.M.H., S.B.); and Department of Cardiology, Deutsches Herzzentrum Berlin (DHZB), Germany (B.P.)
| | - Stefan Bereswill
- From the Department of Cardiology and Pneumology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Germany (C.T., Y.X., K.S., F.S., B.P., U.K., S.V.L.); DZHK (German Center for Cardiovascular Research), partner site Berlin, Germany (C.T., I.M., K.P., B.P., S.V.L.); Berlin-Brandenburg Center for Regenerative Therapies, Charité, University Medicine Berlin, Campus Virchow, Germany (C.T., I.M., K.P., K.M., S.V.L.); Department of Applied Biochemistry, Institute of Biotechnology, Technische Universität Berlin, Germany (S.P., H.F.); Institut Kardiale Diagnostik und Therapie (IKDT), Berlin, Germany (D.L., H.-P.S.); Institut für Mikrobiologie und Infektionsmedizin, Campus Benjamin Franklin, Berlin, Germany (M.M.H., S.B.); and Department of Cardiology, Deutsches Herzzentrum Berlin (DHZB), Germany (B.P.)
| | - Heinz-Peter Schultheiss
- From the Department of Cardiology and Pneumology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Germany (C.T., Y.X., K.S., F.S., B.P., U.K., S.V.L.); DZHK (German Center for Cardiovascular Research), partner site Berlin, Germany (C.T., I.M., K.P., B.P., S.V.L.); Berlin-Brandenburg Center for Regenerative Therapies, Charité, University Medicine Berlin, Campus Virchow, Germany (C.T., I.M., K.P., K.M., S.V.L.); Department of Applied Biochemistry, Institute of Biotechnology, Technische Universität Berlin, Germany (S.P., H.F.); Institut Kardiale Diagnostik und Therapie (IKDT), Berlin, Germany (D.L., H.-P.S.); Institut für Mikrobiologie und Infektionsmedizin, Campus Benjamin Franklin, Berlin, Germany (M.M.H., S.B.); and Department of Cardiology, Deutsches Herzzentrum Berlin (DHZB), Germany (B.P.)
| | - Henry Fechner
- From the Department of Cardiology and Pneumology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Germany (C.T., Y.X., K.S., F.S., B.P., U.K., S.V.L.); DZHK (German Center for Cardiovascular Research), partner site Berlin, Germany (C.T., I.M., K.P., B.P., S.V.L.); Berlin-Brandenburg Center for Regenerative Therapies, Charité, University Medicine Berlin, Campus Virchow, Germany (C.T., I.M., K.P., K.M., S.V.L.); Department of Applied Biochemistry, Institute of Biotechnology, Technische Universität Berlin, Germany (S.P., H.F.); Institut Kardiale Diagnostik und Therapie (IKDT), Berlin, Germany (D.L., H.-P.S.); Institut für Mikrobiologie und Infektionsmedizin, Campus Benjamin Franklin, Berlin, Germany (M.M.H., S.B.); and Department of Cardiology, Deutsches Herzzentrum Berlin (DHZB), Germany (B.P.)
| | - Burkert Pieske
- From the Department of Cardiology and Pneumology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Germany (C.T., Y.X., K.S., F.S., B.P., U.K., S.V.L.); DZHK (German Center for Cardiovascular Research), partner site Berlin, Germany (C.T., I.M., K.P., B.P., S.V.L.); Berlin-Brandenburg Center for Regenerative Therapies, Charité, University Medicine Berlin, Campus Virchow, Germany (C.T., I.M., K.P., K.M., S.V.L.); Department of Applied Biochemistry, Institute of Biotechnology, Technische Universität Berlin, Germany (S.P., H.F.); Institut Kardiale Diagnostik und Therapie (IKDT), Berlin, Germany (D.L., H.-P.S.); Institut für Mikrobiologie und Infektionsmedizin, Campus Benjamin Franklin, Berlin, Germany (M.M.H., S.B.); and Department of Cardiology, Deutsches Herzzentrum Berlin (DHZB), Germany (B.P.)
| | - Uwe Kühl
- From the Department of Cardiology and Pneumology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Germany (C.T., Y.X., K.S., F.S., B.P., U.K., S.V.L.); DZHK (German Center for Cardiovascular Research), partner site Berlin, Germany (C.T., I.M., K.P., B.P., S.V.L.); Berlin-Brandenburg Center for Regenerative Therapies, Charité, University Medicine Berlin, Campus Virchow, Germany (C.T., I.M., K.P., K.M., S.V.L.); Department of Applied Biochemistry, Institute of Biotechnology, Technische Universität Berlin, Germany (S.P., H.F.); Institut Kardiale Diagnostik und Therapie (IKDT), Berlin, Germany (D.L., H.-P.S.); Institut für Mikrobiologie und Infektionsmedizin, Campus Benjamin Franklin, Berlin, Germany (M.M.H., S.B.); and Department of Cardiology, Deutsches Herzzentrum Berlin (DHZB), Germany (B.P.)
| | - Sophie Van Linthout
- From the Department of Cardiology and Pneumology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Germany (C.T., Y.X., K.S., F.S., B.P., U.K., S.V.L.); DZHK (German Center for Cardiovascular Research), partner site Berlin, Germany (C.T., I.M., K.P., B.P., S.V.L.); Berlin-Brandenburg Center for Regenerative Therapies, Charité, University Medicine Berlin, Campus Virchow, Germany (C.T., I.M., K.P., K.M., S.V.L.); Department of Applied Biochemistry, Institute of Biotechnology, Technische Universität Berlin, Germany (S.P., H.F.); Institut Kardiale Diagnostik und Therapie (IKDT), Berlin, Germany (D.L., H.-P.S.); Institut für Mikrobiologie und Infektionsmedizin, Campus Benjamin Franklin, Berlin, Germany (M.M.H., S.B.); and Department of Cardiology, Deutsches Herzzentrum Berlin (DHZB), Germany (B.P.)
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Ursu ON, Beyer T, Sauter M, Fragasso A, Bundschuh S, Klingel K, Munz B. TRAF6: A player in CVB3-induced myocarditis? Cytokine 2017; 122:154143. [PMID: 28886971 DOI: 10.1016/j.cyto.2017.08.023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2017] [Revised: 08/11/2017] [Accepted: 08/28/2017] [Indexed: 11/26/2022]
Abstract
Coxsackievirus B3 (CVB3) is an important inducer of myocarditis, which, in susceptible individuals, can chronify and eventually lead to the development of dilated cardiomyopathy and heart failure. The respective mechanisms are not completely understood. Here, we analyzed expression of the TRAF6 gene, encoding TNF receptor-associated factor 6 (TRAF6), a signal transduction scaffold protein that acts downstream of cytokine receptors, in heart tissue of susceptible and non-susceptible mouse strains. We found that after infection, TRAF6 expression was upregulated in both non-susceptible C57BL/6 wildtype and susceptible A.BY/SnJ and C57BL/6-TLR3 (-/-) mice, however, to different degrees. In infected HeLa cells, we also found moderately elevated TRAF6 levels after infection, in addition, activity of the transcription factor nuclear factor kappa B (NFκB), which can be activated downstream of TRAF6, was strongly enhanced in infected cells. To functionally analyze the role of TRAF6 with regard to infection progression, TRAF6 expression was knocked down in cultured HeLa cells using specific siRNAs. We found that reduction of TRAF6 expression had no effect on NFκB activation in response to infection. Taken together, our data suggest that CVB3 infection enhances TRAF6 levels, however, this induction might not be necessary for infection-induced NFκB activation.
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Affiliation(s)
- Oana N Ursu
- University Hospital Tübingen Medical Clinic, Department of Sports Medicine, Hoppe-Seyler-Str. 6, D-72076 Tübingen, Germany; University Hospital Tübingen, Department of Molecular Pathology, Institute for Pathology and Neuropathology, Liebermeisterstr. 8, D-72076 Tübingen, Germany
| | - Tina Beyer
- University Hospital Tübingen Medical Clinic, Department of Sports Medicine, Hoppe-Seyler-Str. 6, D-72076 Tübingen, Germany; University Hospital Tübingen, Department of Molecular Pathology, Institute for Pathology and Neuropathology, Liebermeisterstr. 8, D-72076 Tübingen, Germany
| | - Martina Sauter
- University Hospital Tübingen, Department of Molecular Pathology, Institute for Pathology and Neuropathology, Liebermeisterstr. 8, D-72076 Tübingen, Germany
| | - Annunziata Fragasso
- University Hospital Tübingen Medical Clinic, Department of Sports Medicine, Hoppe-Seyler-Str. 6, D-72076 Tübingen, Germany
| | - Sandra Bundschuh
- University Hospital Tübingen, Department of Molecular Pathology, Institute for Pathology and Neuropathology, Liebermeisterstr. 8, D-72076 Tübingen, Germany
| | - Karin Klingel
- University Hospital Tübingen, Department of Molecular Pathology, Institute for Pathology and Neuropathology, Liebermeisterstr. 8, D-72076 Tübingen, Germany
| | - Barbara Munz
- University Hospital Tübingen Medical Clinic, Department of Sports Medicine, Hoppe-Seyler-Str. 6, D-72076 Tübingen, Germany.
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Abstract
PURPOSE OF REVIEW With the intention to summarize the currently available evidence on the pathophysiological relevance of inflammation in heart failure, this review addresses the question whether inflammation is a cause or consequence of heart failure, or both. RECENT FINDINGS This review discusses the diversity (sterile, para-inflammation, chronic inflammation) and sources of inflammation and gives an overview of how inflammation (local versus systemic) can trigger heart failure. On the other hand, the review is outlined how heart failure-associated wall stress and signals released by stressed, malfunctioning, or dead cells (DAMPs: e.g., mitochondrial DNA, ATP, S100A8, matricellular proteins) induce cardiac sterile inflammation and how heart failure provokes inflammation in various peripheral tissues in a direct (inflammatory) and indirect (hemodynamic) manner. The crosstalk between the heart and peripheral organs (bone marrow, spleen, gut, adipose tissue) is outlined and the importance of neurohormonal mechanisms including the renin angiotensin aldosteron system and the ß-adrenergic nervous system in inflammation and heart failure is discussed. Inflammation and heart failure are strongly interconnected and mutually reinforce each other. This indicates the difficulty to counteract inflammation and heart failure once this chronic vicious circle has started and points out the need to control the inflammatory process at an early stage avoiding chronic inflammation and heart failure. The diversity of inflammation further addresses the need for a tailored characterization of inflammation enabling differentiation of inflammation and subsequent target-specific strategies. It is expected that the characterization of the systemic and/or cardiac immune profile will be part of precision medicine in the future of cardiology.
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Affiliation(s)
- Sophie Van Linthout
- Berlin-Brandenburg Center for Regenerative Therapies, Charité – Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Carsten Tschöpe
- Berlin-Brandenburg Center for Regenerative Therapies, Charité – Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
- Department of Cardiology, Campus Virchow Klinikum, Charité – Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
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28
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Cardiac Function Remains Impaired Despite Reversible Cardiac Remodeling after Acute Experimental Viral Myocarditis. J Immunol Res 2017; 2017:6590609. [PMID: 28352641 PMCID: PMC5352897 DOI: 10.1155/2017/6590609] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Revised: 12/01/2016] [Accepted: 12/15/2016] [Indexed: 12/15/2022] Open
Abstract
Background. Infection with Coxsackievirus B3 induces myocarditis. We aimed to compare the acute and chronic phases of viral myocarditis to identify the immediate effects of cardiac inflammation as well as the long-term effects after resolved inflammation on cardiac fibrosis and consequently on cardiac function. Material and Methods. We infected C57BL/6J mice with Coxsackievirus B3 and determined the hemodynamic function 7 as well as 28 days after infection. Subsequently, we analyzed viral burden and viral replication in the cardiac tissue as well as the expression of cytokines and matrix proteins. Furthermore, cardiac fibroblasts were infected with virus to investigate if viral infection alone induces profibrotic signaling. Results. Severe cardiac inflammation was determined and cardiac fibrosis was consistently colocalized with inflammation during the acute phase of myocarditis. Declined cardiac inflammation but no significantly improved hemodynamic function was observed 28 days after infection. Interestingly, cardiac fibrosis declined to basal levels as well. Both cardiac inflammation and fibrosis were reversible, whereas the hemodynamic function remains impaired after healed viral myocarditis in C57BL/6J mice.
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29
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Stephenson E, Savvatis K, Mohiddin SA, Marelli-Berg FM. T-cell immunity in myocardial inflammation: pathogenic role and therapeutic manipulation. Br J Pharmacol 2016; 174:3914-3925. [PMID: 27590129 DOI: 10.1111/bph.13613] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2016] [Revised: 08/11/2016] [Accepted: 08/16/2016] [Indexed: 12/13/2022] Open
Abstract
T-cell-mediated immunity has been linked not only to a variety of heart diseases, including classic inflammatory diseases such as myocarditis and post-myocardial infarction (Dressler's) syndrome, but also to conditions without an obvious inflammatory component such as idiopathic dilated cardiomyopathy and hypertensive cardiomyopathy. It has been recently proposed that in all these conditions, the heart becomes the focus of T-cell-mediated autoimmune inflammation following ischaemic or infectious injury. For example, in acute myocarditis, an inflammatory disease of heart muscle, T-cell responses are thought to arise as a consequence of a viral infection. In a number of patients, persistent T-cell-mediated responses in acute viral myocarditis can lead to autoimmunity and chronic cardiac inflammation resulting in dilated cardiomyopathy. In spite of the major progress made in understanding the mechanisms of pathogenic T-cell responses, effective and safe therapeutic targeting of the immune system in chronic inflammatory diseases of the heart has not yet been developed due to the lack of specific diagnostic and prognostic biomarkers at an early stage. This has also prevented the identification of targets for patient-tailored immunomodulatory therapies that are both disease- and organ-selective. In this review, we discuss current knowledge of the development and functional characteristics of pathogenic T-cell-mediated immune responses in the heart, and, in particular, in myocarditis, as well as recent advances in experimental models which have the potential to translate into heart-selective immunomodulation. LINKED ARTICLES This article is part of a themed section on Targeting Inflammation to Reduce Cardiovascular Disease Risk. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.22/issuetoc and http://onlinelibrary.wiley.com/doi/10.1111/bcp.v82.4/issuetoc.
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Affiliation(s)
- E Stephenson
- William Harvey Research Institute, London, UK.,Barts and The London School of Medicine, London, UK
| | - K Savvatis
- William Harvey Research Institute, London, UK.,Barts and The London School of Medicine, London, UK.,Department of Cardiology, Barts Heart Centre, St. Bartholomew NHS Trust, London, UK
| | - S A Mohiddin
- William Harvey Research Institute, London, UK.,Barts and The London School of Medicine, London, UK.,Department of Cardiology, Barts Heart Centre, St. Bartholomew NHS Trust, London, UK
| | - F M Marelli-Berg
- William Harvey Research Institute, London, UK.,Barts and The London School of Medicine, London, UK
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Yang Y, Lv J, Jiang S, Ma Z, Wang D, Hu W, Deng C, Fan C, Di S, Sun Y, Yi W. The emerging role of Toll-like receptor 4 in myocardial inflammation. Cell Death Dis 2016; 7:e2234. [PMID: 27228349 PMCID: PMC4917669 DOI: 10.1038/cddis.2016.140] [Citation(s) in RCA: 245] [Impact Index Per Article: 27.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2016] [Revised: 03/25/2016] [Accepted: 04/12/2016] [Indexed: 12/17/2022]
Abstract
Toll-like receptors (TLRs) are a family of pattern recognition receptors involved in cardiovascular diseases. Notably, numerous studies have demonstrated that TLR4 activates the expression of several of pro-inflammatory cytokine genes that play pivotal roles in myocardial inflammation, particularly myocarditis, myocardial infarction, ischemia-reperfusion injury, and heart failure. In addition, TLR4 is an emerging target for anti-inflammatory therapies. Given the significance of TLR4, it would be useful to summarize the current literature on the molecular mechanisms and roles of TLR4 in myocardial inflammation. Thus, in this review, we first introduce the basic knowledge of the TLR4 gene and describe the activation and signaling pathways of TLR4 in myocardial inflammation. Moreover, we highlight the recent progress of research on the involvement of TLR4 in myocardial inflammation. The information reviewed here may be useful to further experimental research and to increase the potential of TLR4 as a therapeutic target.
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Affiliation(s)
- Y Yang
- Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi'an 710032, China
- Department of Thoracic and Cardiovascular Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, Jiangsu 210008, China
- Department of Biomedical Engineering, The Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China
| | - J Lv
- Department of Biomedical Engineering, The Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China
| | - S Jiang
- Department of Aerospace Medicine, The Fourth Military Medical University, Xi'an 710032, China
| | - Z Ma
- Department of Thoracic Surgery, Tangdu Hospital, The Fourth Military Medical University, 1 Xinsi Road, Xi'an 710038, China
| | - D Wang
- Department of Thoracic and Cardiovascular Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, Jiangsu 210008, China
| | - W Hu
- Department of Biomedical Engineering, The Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China
| | - C Deng
- Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi'an 710032, China
| | - C Fan
- Department of Thoracic Surgery, Tangdu Hospital, The Fourth Military Medical University, 1 Xinsi Road, Xi'an 710038, China
| | - S Di
- Department of Thoracic Surgery, Tangdu Hospital, The Fourth Military Medical University, 1 Xinsi Road, Xi'an 710038, China
| | - Y Sun
- Department of Geriatrics, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi'an 710032, China
| | - W Yi
- Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi'an 710032, China
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Ullah MO, Sweet MJ, Mansell A, Kellie S, Kobe B. TRIF-dependent TLR signaling, its functions in host defense and inflammation, and its potential as a therapeutic target. J Leukoc Biol 2016; 100:27-45. [PMID: 27162325 DOI: 10.1189/jlb.2ri1115-531r] [Citation(s) in RCA: 148] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2015] [Accepted: 04/04/2016] [Indexed: 12/16/2022] Open
Abstract
Toll/IL-1R domain-containing adaptor-inducing IFN-β (TRIF)-dependent signaling is required for TLR-mediated production of type-I IFN and several other proinflammatory mediators. Various pathogens target the signaling molecules and transcriptional regulators acting in the TRIF pathway, thus demonstrating the importance of this pathway in host defense. Indeed, the TRIF pathway contributes to control of both viral and bacterial pathogens through promotion of inflammatory mediators and activation of antimicrobial responses. TRIF signaling also has both protective and pathologic roles in several chronic inflammatory disease conditions, as well as an essential function in wound-repair processes. Here, we review our current understanding of the regulatory mechanisms that control TRIF-dependent TLR signaling, the role of the TRIF pathway in different infectious and noninfectious pathologic states, and the potential for manipulating TRIF-dependent TLR signaling for therapeutic benefit.
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Affiliation(s)
- M Obayed Ullah
- School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Queensland, Australia; Institute for Molecular Bioscience, Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Queensland, Australia
| | - Matthew J Sweet
- Institute for Molecular Bioscience, Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Queensland, Australia; Institute for Molecular Bioscience, Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, Queensland, Australia; and
| | - Ashley Mansell
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Monash University, Melbourne, Victoria, Australia
| | - Stuart Kellie
- School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Queensland, Australia; Institute for Molecular Bioscience, Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Queensland, Australia
| | - Bostjan Kobe
- School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Queensland, Australia; Institute for Molecular Bioscience, Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Queensland, Australia;
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Lafferty EI, Wiltshire SA, Angers I, Vidal SM, Qureshi ST. Unc93b1 -Dependent Endosomal Toll-Like Receptor Signaling Regulates Inflammation and Mortality during Coxsackievirus B3 Infection. J Innate Immun 2015; 7:315-30. [PMID: 25675947 DOI: 10.1159/000369342] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2014] [Accepted: 10/26/2014] [Indexed: 12/24/2022] Open
Abstract
Coxsackievirus strain B serotype 3 (CVB3)-induced myocarditis is an important human disease that causes permanent tissue damage and can lead to death from acute infection or long-term morbidity caused by chronic inflammation. The timing and magnitude of immune activation following CVB3 infection can mediate a positive host outcome or increase tissue pathology. To better elucidate the role of endosomal Toll-like receptor (TLR) signaling in acute CVB3 infection, we studied mice with a loss-of-function mutation, known as Letr for 'loss of endosomal TLR response', in Unc93b1, which is a chaperone protein for TLR3, TLR7 and TLR9. Using Unc93b1(Letr/)(Letr) mice, we determined that Unc93b1-dependent TLR activation was essential for the survival of acute CVB3-induced myocarditis. We also determined that a lack of endosomal TLR signaling was associated with a higher viral load in target organs and that it increased inflammation, necrosis and fibrosis in cardiac tissue. Loss of Unc93b1 function was also associated with increased cardiac expression of Ifn-b and markers of tissue injury and fibrosis including Lcn2 and Serpina3n early after CVB3 infection. These observations establish a significant role for Unc93b1 in the regulation of the host inflammatory response to CVB3 infection and also reveal potential mediators of host tissue damage that merit further investigation in acute viral myocarditis.
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Affiliation(s)
- Erin I Lafferty
- Meakins-Christie Laboratories, McGill University, Montréal, Qué., Canada
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Abstract
Viral myocarditis is estimated to cause ~20% of sudden death in people under the age of 40. A variety of viruses have been found to cause myocarditis including coxsackievirus B3 (CVB3). Many studies have been performed with CVB3 because there is a mouse model of CVB3-induced myocarditis. Studies have shown that the TLR3-IFNβ pathway plays a central role in the innate immune response to CVB3 infection. Our laboratory studies the role of protease activated receptors (PAR) in different biological responses including viral infection. We examined the effect of a deficiency in either PAR1 or PAR2 on CVB3-induced myocarditis. Interestingly, we found that PAR1 knockout mice had increased cardiac injury whereas PAR2 knockout mice had decreased cardiac injury. Our studies support the notion that PARs modulate the innate immune response and can have both positive and negative effects on TLR-dependent responses.
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Affiliation(s)
- Nigel Mackman
- Department of Medicine, Division of Hematology and Oncology, UNC McAllister Heart Institute, University of North Carolina at Chapel Hill, 98 Manning Drive Campus Box 7035, Chapel Hill, NC, USA.
| | - Silvio Antoniak
- Department of Medicine, Division of Hematology and Oncology, UNC McAllister Heart Institute, University of North Carolina at Chapel Hill, 98 Manning Drive Campus Box 7035, Chapel Hill, NC, USA
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Ubiquitin-Like Protein ISG15 (Interferon-Stimulated Gene of 15 kDa) in Host Defense Against Heart Failure in a Mouse Model of Virus-Induced Cardiomyopathy. Circulation 2014; 130:1589-600. [DOI: 10.1161/circulationaha.114.009847] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Background—
Common causative agents in the development of inflammatory cardiomyopathy include cardiotropic viruses such as coxsackievirus B3 (CVB3). Here, we investigated the role of the ubiquitin-like modifier interferon-stimulated gene of 15 kDa (ISG15) in the pathogenesis of viral cardiomyopathy.
Methods and Results—
In CVB3-infected mice, the absence of protein modification with ISG15 was accompanied by a profound exacerbation of myocarditis and by a significant increase in mortality and heart failure. We found that ISG15 in cardiomyocytes contributed significantly to the suppression of viral replication. In the absence of an intact ISG15 system, virus titers were markedly elevated by postinfection day 8, and viral RNA persisted in ISG15
−/−
mice at postinfection day 28. Ablation of the ISG15 protein modification system in CVB3 infection predisposed mice to long-term disease with deposition of collagen fibers, all leading to inflammatory cardiomyopathy. We found that ISG15 acts as part of the intrinsic immunity in cardiomyocytes and detected no significant effects of ISG15 modification on the cellular immune response. ISG15 modification of CVB3 2A protease counterbalanced CVB3-induced cleavage of the host cell eukaryotic initiation factor of translation eIF4G in cardiomyocytes, thereby counterbalancing the shutoff of host cell translation in CVB3 infection. We demonstrate that ISG15 suppressed infectious virus yield in human cardiac myocytes and the induction of ISG15 in patients with viral cardiomyopathy.
Conclusions—
The ISG15 conjugation system represents a critical innate response mechanism in cardiomyocytes to fight the battle against invading pathogens, limiting inflammatory cardiomyopathy, heart failure, and death. Interference with the ISG15 system might be a novel therapeutic approach in viral cardiomyopathy.
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Lindner D, Li J, Savvatis K, Klingel K, Blankenberg S, Tschöpe C, Westermann D. Cardiac fibroblasts aggravate viral myocarditis: cell specific coxsackievirus B3 replication. Mediators Inflamm 2014; 2014:519528. [PMID: 25374444 PMCID: PMC4211177 DOI: 10.1155/2014/519528] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2014] [Revised: 08/22/2014] [Accepted: 08/25/2014] [Indexed: 12/29/2022] Open
Abstract
Myocarditis is an inflammatory disease caused by viral infection. Different subpopulations of leukocytes enter the cardiac tissue and lead to severe cardiac inflammation associated with myocyte loss and remodeling. Here, we study possible cell sources for viral replication using three compartments of the heart: fibroblasts, cardiomyocytes, and macrophages. We infected C57BL/6j mice with Coxsackievirus B3 (CVB3) and detected increased gene expression of anti-inflammatory and antiviral cytokines in the heart. Subsequently, we infected cardiac fibroblasts, cardiomyocytes, and macrophages with CVB3. Due to viral infection, the expression of TNF-α, IL-6, MCP-1, and IFN-β was significantly increased in cardiac fibroblasts compared to cardiomyocytes or macrophages. We found that in addition to cardiomyocytes cardiac fibroblasts were infected by CVB3 and displayed a higher virus replication (132-fold increase) compared to cardiomyocytes (14-fold increase) between 6 and 24 hours after infection. At higher virus concentrations, macrophages are able to reduce the viral copy number. At low virus concentration a persistent virus infection was determined. Therefore, we suggest that cardiac fibroblasts play an important role in the pathology of CVB3-induced myocarditis and are another important contributor of virus replication aggravating myocarditis.
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MESH Headings
- Animals
- Cells, Cultured
- Coxsackievirus Infections/pathology
- Coxsackievirus Infections/physiopathology
- Coxsackievirus Infections/virology
- Cytokines/genetics
- Enterovirus B, Human/genetics
- Enterovirus B, Human/pathogenicity
- Enterovirus B, Human/physiology
- Fibroblasts/immunology
- Fibroblasts/pathology
- Fibroblasts/virology
- Gene Expression
- Genome, Viral
- Heart/virology
- Macrophages/immunology
- Macrophages/pathology
- Macrophages/virology
- Male
- Mice
- Mice, Inbred C57BL
- Myocarditis/pathology
- Myocarditis/physiopathology
- Myocarditis/virology
- Myocardium/immunology
- Myocardium/pathology
- Myocytes, Cardiac/immunology
- Myocytes, Cardiac/pathology
- Myocytes, Cardiac/virology
- Ventricular Function, Left
- Viral Load
- Virus Replication
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Affiliation(s)
- Diana Lindner
- Clinic for General and Interventional Cardiology, University Heart Center Hamburg, Martinistraße 52, 20246 Hamburg, Germany
- German Center for Cardiovascular Research (DZHK), Partner Sites, Hamburg/Kiel/Lübeck, Germany
| | - Jia Li
- Clinic for General and Interventional Cardiology, University Heart Center Hamburg, Martinistraße 52, 20246 Hamburg, Germany
| | - Konstantinos Savvatis
- Department of Cardiology and Pneumology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin (CBF), Berlin, Germany
| | - Karin Klingel
- Department of Molecular Pathology, Institute for Pathology, Eberhard Karls University of Tübingen, Tübingen, Germany
| | - Stefan Blankenberg
- Clinic for General and Interventional Cardiology, University Heart Center Hamburg, Martinistraße 52, 20246 Hamburg, Germany
- German Center for Cardiovascular Research (DZHK), Partner Sites, Hamburg/Kiel/Lübeck, Germany
| | - Carsten Tschöpe
- Department of Cardiology and Pneumology, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin (CBF), Berlin, Germany
- German Center for Cardiovascular Research (DZHK), Partner Sites, Berlin, Germany
| | - Dirk Westermann
- Clinic for General and Interventional Cardiology, University Heart Center Hamburg, Martinistraße 52, 20246 Hamburg, Germany
- German Center for Cardiovascular Research (DZHK), Partner Sites, Hamburg/Kiel/Lübeck, Germany
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Van Linthout S, Tschöpe C, Schultheiss HP. Lack in Treatment Options for Virus-Induced Inflammatory Cardiomyopathy. Circ Res 2014; 115:540-1. [DOI: 10.1161/circresaha.114.304951] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Sophie Van Linthout
- From the Berlin-Brandenburg Center for Regenerative Therapies, Charité, University Medicine Berlin, Campus Virchow Clinic, Berlin, Germany (S.V.L., C.T.); and Department of Cardiology and Pneumology, Charité, University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany (H.-P.S., C.T.)
| | - Carsten Tschöpe
- From the Berlin-Brandenburg Center for Regenerative Therapies, Charité, University Medicine Berlin, Campus Virchow Clinic, Berlin, Germany (S.V.L., C.T.); and Department of Cardiology and Pneumology, Charité, University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany (H.-P.S., C.T.)
| | - Heinz-Peter Schultheiss
- From the Berlin-Brandenburg Center for Regenerative Therapies, Charité, University Medicine Berlin, Campus Virchow Clinic, Berlin, Germany (S.V.L., C.T.); and Department of Cardiology and Pneumology, Charité, University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany (H.-P.S., C.T.)
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Wagner KB, Felix SB, Riad A. Innate immune receptors in heart failure: Side effect or potential therapeutic target? World J Cardiol 2014; 6:791-801. [PMID: 25228958 PMCID: PMC4163708 DOI: 10.4330/wjc.v6.i8.791] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2014] [Revised: 04/18/2014] [Accepted: 06/11/2014] [Indexed: 02/06/2023] Open
Abstract
Heart failure (HF) is a leading cause of mortality and morbidity in western countries and occasions major expenses for public health systems. Although optimal medical treatment is widely available according to current guidelines, the prognosis of patients with HF is still poor. Despite the etiology of the disease, increased systemic or cardiac activation of the innate immune system is well documented in several types of HF. In some cases there is evidence of an association between innate immune activation and clinical outcome of patients with this disease. However, the few large trials conducted with the use of anti-inflammatory medication in HF have not revealed its benefits. Thus, greater understanding of the relationship between alteration in the immune system and development and progression of HF is urgently necessary: prior to designing therapeutic interventions that target pathological inflammatory processes in preventing harmful cardiac effects of immune modulatory therapy. In this regard, relatively recently discovered receptors of the innate immune system, i.e., namely toll-like receptors (TLRs) and nod-like receptors (NLRs)-are the focus of intense cardiovascular research. These receptors are main up-stream regulators of cytokine activation. This review will focus on current knowledge of the role of TLRs and NLRs, as well as on downstream cytokine activation, and will discuss potential therapeutic implications.
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Role of protease-activated receptors for the innate immune response of the heart. Trends Cardiovasc Med 2014; 24:249-55. [PMID: 25066486 DOI: 10.1016/j.tcm.2014.06.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2014] [Revised: 06/04/2014] [Accepted: 06/21/2014] [Indexed: 02/07/2023]
Abstract
Protease-activated receptors (PARs) are a family of G-protein-coupled receptors with a unique activation mechanism via cleavage by the serine proteases of the coagulation cascade, immune cell-released proteases, and proteases from pathogens. Pathogens, such as viruses and bacteria, cause myocarditis and heart failure and PAR1 was shown to positively regulate the anti-viral innate immune response via interferon β during virus-induced myocarditis. In contrast, PAR2 negatively regulated the innate immune response and inhibited the interferon β expression. Thus, PARs play a central role for the innate immune response in the heart.
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Glaubitz M, Block S, Witte J, Empen K, Gross S, Schlicht R, Weitmann K, Klingel K, Kandolf R, Hoffmann W, Gottschalk KE, Busch M, Dörr M, Helm CA, Felix SB, Riad A. Stiffness of left ventricular cardiac fibroblasts is associated with ventricular dilation in patients with recent-onset nonischemic and nonvalvular cardiomyopathy. Circ J 2014; 78:1693-700. [PMID: 24899232 DOI: 10.1253/circj.cj-13-1188] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
BACKGROUND Ventricular dilation is known as a pivotal predictor in recent-onset cardiomyopathy (ROCM), but its pathophysiology is not fully understood. In the present study we investigated whether single-cell stiffness of right and left ventricular-derived fibroblasts has an effect on cardiac phenotype in patients with ROCM. METHODS AND RESULTS Patients with endomyocardial biopsy-proven ROCM were included (n=10). Primary cardiac fibroblasts (CFBs) were cultured from left and right ventricular endomyocardial biopsies and their single-cell stiffness was analyzed by quantification of Young's modulus using colloidal probe atomic force microscopy. Cardiac fibrosis was analyzed by Masson's trichrome staining. CFBs from the left ventricle showed significantly decreased stiffness when compared with CFBs from the right ventricle, indexed by decreased stiffness (Young's modulus 3,374±389 vs. 4,837±690 Pa; P<0.05). Young's modulus of CFBs derived from the left ventricle correlated negatively with the left ventricular end-diastolic dimension derived from 2-dimensional echocardiography (R(2)=0.77; P<0.01). Neither left nor right ventricular fibrosis correlated with the respective ventricular dimensions. CONCLUSIONS Our data suggest that a decrease in single-cell stiffness of left ventricular fibroblasts could trigger left ventricular dilation in patients with ROCM. This implies a new potential mechanism for the ventricular dilation with this disease.
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Affiliation(s)
- Michael Glaubitz
- ZIK-HIKE - Zentrum für Innovationskompetenz "Humorale Immunreaktionen bei kardiovaskulären Erkrankungen", University Medicine Greifswald
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40
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Xiang Z, Li L, Lei X, Zhou H, Zhou Z, He B, Wang J. Enterovirus 68 3C protease cleaves TRIF to attenuate antiviral responses mediated by Toll-like receptor 3. J Virol 2014; 88:6650-9. [PMID: 24672048 PMCID: PMC4054379 DOI: 10.1128/jvi.03138-13] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2013] [Accepted: 03/24/2014] [Indexed: 12/14/2022] Open
Abstract
UNLABELLED Human enterovirus 68 (EV68) is a member of the EV-D species, which belongs to the EV genus of the Picornaviridae family. Over the past several years, there have been increasingly documented outbreaks of respiratory disease associated with EV68. As a globally emerging pathogen, EV68 infects both adults and children. However, the molecular basis of EV68 pathogenesis is unknown. Here we report that EV68 inhibits Toll-like receptor 3 (TLR3)-mediated innate immune responses by targeting the TIR domain-containing adaptor inducing beta interferon (TRIF). In infected HeLa cells, EV68 inhibits poly(I·C)-induced interferon regulatory factor 3 (IRF3) activation and beta interferon (IFN-β) expression. Further investigations revealed that TRIF, a critical adaptor downstream of TLR3, is targeted by EV68. When expressed alone, 3C(pro), an EV68-encoded protease, cleaves TRIF. 3C(pro) mediates TRIF cleavage at Q312 and Q653, which are sites in the amino- and carboxyl-terminal domains, respectively. This cleavage relies on 3C(pro)'s cysteine protease activity. Cleavage of TRIF abolishes the capacity of TRIF to activate NF-κB and IFN-β signaling. These results suggest that control of TRIF by 3C(pro) may be a mechanism by which EV68 subverts host innate immune responses. IMPORTANCE EV68 is a globally emerging pathogen, but the molecular basis of EV68 pathogenesis is unclear. Here we report that EV68 inhibits TLR3-mediated innate immune responses by targeting TRIF. Further investigations revealed that TRIF is cleaved by 3C(pro). These results suggest that control of TRIF by 3C(pro) may be a mechanism by which EV68 impairs type I IFN production in response to TLR3 activation.
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Affiliation(s)
- Zichun Xiang
- MOH Key Laboratory of Systems Biology of Pathogens and Christophe Mérieux Laboratory, IPB, CAMS-Fondation Mérieux, Institute of Pathogen Biology (IPB), Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College, Beijing, People's Republic of China
| | - Linlin Li
- MOH Key Laboratory of Systems Biology of Pathogens and Christophe Mérieux Laboratory, IPB, CAMS-Fondation Mérieux, Institute of Pathogen Biology (IPB), Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College, Beijing, People's Republic of China
| | - Xiaobo Lei
- MOH Key Laboratory of Systems Biology of Pathogens and Christophe Mérieux Laboratory, IPB, CAMS-Fondation Mérieux, Institute of Pathogen Biology (IPB), Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College, Beijing, People's Republic of China
| | - Hongli Zhou
- MOH Key Laboratory of Systems Biology of Pathogens and Christophe Mérieux Laboratory, IPB, CAMS-Fondation Mérieux, Institute of Pathogen Biology (IPB), Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College, Beijing, People's Republic of China
| | - Zhuo Zhou
- MOH Key Laboratory of Systems Biology of Pathogens and Christophe Mérieux Laboratory, IPB, CAMS-Fondation Mérieux, Institute of Pathogen Biology (IPB), Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College, Beijing, People's Republic of China
| | - Bin He
- Department of Microbiology and Immunology, College of Medicine, University of Illinois, Chicago, Illinois, USA
| | - Jianwei Wang
- MOH Key Laboratory of Systems Biology of Pathogens and Christophe Mérieux Laboratory, IPB, CAMS-Fondation Mérieux, Institute of Pathogen Biology (IPB), Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College, Beijing, People's Republic of China
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41
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Jenke A, Holzhauser L, Löbel M, Savvatis K, Wilk S, Weithäuser A, Pinkert S, Tschöpe C, Klingel K, Poller W, Scheibenbogen C, Schultheiss HP, Skurk C. Adiponectin promotes coxsackievirus B3 myocarditis by suppression of acute anti-viral immune responses. Basic Res Cardiol 2014; 109:408. [DOI: 10.1007/s00395-014-0408-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2013] [Accepted: 03/14/2014] [Indexed: 10/25/2022]
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Abstract
The coagulation cascade is activated during viral infections. This response may be part of the host defense system to limit spread of the pathogen. However, excessive activation of the coagulation cascade can be deleterious. In fact, inhibition of the tissue factor/factor VIIa complex reduced mortality in a monkey model of Ebola hemorrhagic fever. Other studies showed that incorporation of tissue factor into the envelope of herpes simplex virus increases infection of endothelial cells and mice. Furthermore, binding of factor X to adenovirus serotype 5 enhances infection of hepatocytes but also increases the activation of the innate immune response to the virus. Coagulation proteases activate protease-activated receptors (PARs). Interestingly, we and others found that PAR1 and PAR2 modulate the immune response to viral infection. For instance, PAR1 positively regulates TLR3-dependent expression of the antiviral protein interferon β, whereas PAR2 negatively regulates expression during coxsackievirus group B infection. These studies indicate that the coagulation cascade plays multiple roles during viral infections.
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43
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In vivo ablation of type I interferon receptor from cardiomyocytes delays coxsackieviral clearance and accelerates myocardial disease. J Virol 2014; 88:5087-99. [PMID: 24574394 DOI: 10.1128/jvi.00184-14] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
UNLABELLED Acute coxsackievirus B3 (CVB3) infection is one of the most prevalent causes of acute myocarditis, a disease that frequently is identified only after the sudden death of apparently healthy individuals. CVB3 infects cardiomyocytes, but the infection is highly focal, even in the absence of a strong adaptive immune response, suggesting that virus spread within the heart may be tightly constrained by the innate immune system. Type I interferons (T1IFNs) are an obvious candidate, and T1IFN receptor (T1IFNR) knockout mice are highly susceptible to CVB3 infection, succumbing within a few days of challenge. Here, we investigated the role of T1IFNs in the heart using a mouse model in which the T1IFNR gene can be ablated in vivo, specifically in cardiomyocytes. We found that T1IFN signaling into cardiomyocytes contributed substantially to the suppression of viral replication and infectious virus yield in the heart; in the absence of such signaling, virus titers were markedly elevated by day 3 postinfection (p.i.) and remained high at day 12 p.i., a time point at which virus was absent from genetically intact littermates, suggesting that the T1IFN-unresponsive cardiomyocytes may act as a safe haven for the virus. Nevertheless, in these mice the myocardial infection remained highly focal, despite the cardiomyocytes' inability to respond to T1IFN, indicating that other factors, as yet unidentified, are sufficient to prevent the more widespread dissemination of the infection throughout the heart. The absence of T1IFN signaling into cardiomyocytes also was accompanied by a profound acceleration and exacerbation of myocarditis and by a significant increase in mortality. IMPORTANCE Acute coxsackievirus B3 (CVB3) infection is one of the most common causes of acute myocarditis, a serious and sometimes fatal disease. To optimize treatment, it is vital that we identify the immune factors that limit virus spread in the heart and other organs. Type I interferons play a key role in controlling many virus infections, but it has been suggested that they may not directly impact CVB3 infection within the heart. Here, using a novel line of transgenic mice, we show that these cytokines signal directly into cardiomyocytes, limiting viral replication, myocarditis, and death.
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44
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Abstract
PURPOSE OF REVIEW To review how autoimmunity is induced in viral myocarditis. RECENT FINDINGS Clinical and experimental myocarditis follows microbial infections, but autoimmunity to cardiac antigens leads to heart failure since infected myocytes are sparse and virus clearance is rapid. In mice, CD4+ T cells specific for cardiac alpha myosin heavy chain (αMYHC) cause myocarditis and mice tolerized to αMYHC are protected from virus challenge proving pathogenesis depends upon autoimmunity. Most importantly, multiple microbes share the same mimicking epitope with αMYHC. Serial infections with very different microbes could result in memory responses to the shared epitope leading to aggressive and severe heart failure. A similar phenomenon may explain autoimmune diseases with suspected infectious causes, where specific pathogens have not been identified. Production of the relevant cardiac epitope for antigen presentation requires more than myosin release from dead myocytes. Otherwise, myocarditis would commonly follow myocardial infarcts. The inherent nature of the innate immune response associated with viral infections in the heart is crucial to cardiac epitope expression. SUMMARY Antigenic mimicry between microbes and cardiac proteins causes autoimmunity in myocarditis. Characteristics of innate immunity associated with cardiac infection determine relevant epitope expression (cryptic epitopes).
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Chen C, Feng Y, Zou L, Wang L, Chen HH, Cai JY, Xu JM, Sosnovik DE, Chao W. Role of extracellular RNA and TLR3-Trif signaling in myocardial ischemia-reperfusion injury. J Am Heart Assoc 2014; 3:e000683. [PMID: 24390148 PMCID: PMC3959703 DOI: 10.1161/jaha.113.000683] [Citation(s) in RCA: 124] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Background Toll‐like receptor 3 (TLR3) was originally identified as the receptor for viral RNA and represents a major host antiviral defense mechanism. TLR3 may also recognize extracellular RNA (exRNA) released from injured tissues under certain stress conditions. However, a role for exRNA and TLR3 in the pathogenesis of myocardial ischemic injury has not been tested. This study examined the role of exRNA and TLR3 signaling in myocardial infarction (MI), apoptosis, inflammation, and cardiac dysfunction during ischemia‐reperfusion (I/R) injury. Methods and Results Wild‐type (WT), TLR3−/−, Trif−/−, and interferon (IFN) α/β receptor‐1 deficient (IFNAR1−/−) mice were subjected to 45 minutes of coronary artery occlusion and 24 hours of reperfusion. Compared with WT, TLR3−/− or Trif−/− mice had smaller MI and better preserved cardiac function. Surprisingly, unlike TLR(2/4)‐MyD88 signaling, lack of TLR3‐Trif signaling had no impact on myocardial cytokines or neutrophil recruitment after I/R, but myocardial apoptosis was significantly attenuated in Trif−/− mice. Deletion of the downstream IFNAR1 had no effect on infarct size. Importantly, hypoxia and I/R led to release of RNA including microRNA from injured cardiomyocytes and ischemic heart, respectively. Necrotic cardiomyocytes induced a robust and dose‐dependent cytokine response in cultured cardiomyocytes, which was markedly reduced by RNase but not DNase, and partially blocked in TLR3‐deficient cardiomyocytes. In vivo, RNase administration reduced serum RNA level, attenuated myocardial cytokine production, leukocytes infiltration and apoptosis, and conferred cardiac protection against I/R injury. Conclusion TLR3‐Trif signaling represents an injurious pathway during I/R. Extracellular RNA released during I/R may contribute to myocardial inflammation and infarction.
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Affiliation(s)
- Chan Chen
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital
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Antoniak S, Mackman N. Coagulation, protease-activated receptors, and viral myocarditis. J Cardiovasc Transl Res 2013; 7:203-11. [PMID: 24203054 DOI: 10.1007/s12265-013-9515-7] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2013] [Accepted: 10/16/2013] [Indexed: 12/29/2022]
Abstract
The coagulation protease cascade plays an essential role in hemostasis. In addition, a clot contributes to host defense by limiting the spread of pathogens. Coagulation proteases induce intracellular signaling by cleavage of cell surface receptors called protease-activated receptors (PARs). These receptors allow cells to sense changes in the extracellular environment, such as infection. Viruses activate the coagulation cascade by inducing tissue factor expression and by disrupting the endothelium. Virus infection of the heart can cause myocarditis, cardiac remodeling, and heart failure. A recent study using a mouse model have shown that tissue factor, thrombin, and PAR-1 signaling all positively regulate the innate immune during viral myocarditis. In contrast, PAR-2 signaling was found to inhibit interferon-β expression and the innate immune response. These observations suggest that anticoagulants may impair the innate immune response to viral infection and that inhibition of PAR-2 may be a new strategy to reduce viral myocarditis.
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Affiliation(s)
- Silvio Antoniak
- Division of Hematology and Oncology, Department of Medicine, UNC McAllister Heart Institute, University of North Carolina at Chapel Hill, 98 Manning Drive, Campus Box 7035, Chapel Hill, NC, 27599, USA,
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Yang C, Li Q, Su J, Chen X, Wang Y, Peng L. Identification and functional characterizations of a novel TRIF gene from grass carp (Ctenopharyngodon idella). DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2013; 41:222-229. [PMID: 23732407 DOI: 10.1016/j.dci.2013.05.018] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/01/2013] [Revised: 05/23/2013] [Accepted: 05/24/2013] [Indexed: 06/02/2023]
Abstract
Toll/interleukin-1 receptor (TIR) domain containing adapter inducing interferon-β (TRIF) is an adapter in responding to activation of some toll-like receptors (TLRs), which provides early clearance of viral and bacterial pathogens. Here we identified and characterized a full-length genomic sequence of TRIF gene from grass carp Ctenopharyngodon idella (designated as CiTRIF). CiTRIF genomic sequence consists of 3534 base pairs (bp), containing 5' flank sequence (496 bp) and unique intron (815 bp). The full-length cDNA sequence is 2241 bp, including 5' untranslated region (UTR) of 352 bp, 3' UTR of 209 bp, and an open reading frame of 1680 bp encoding a polypeptide of 559 amino acids with an estimated molecular weight of 62.643 kDa and a predicted isoelectric point of 5.71. The deduced amino acid sequence just contains TIR domain, and is most similar to the zebrafish (Danio rerio) TRIF sequence with an identity of 64%. CiTRIF exhibits sequence divergence from its orthologs. Promoter region was predicted and promoter activity was verified. mRNA expression of CiTRIF gene is widespread in 15 tissues investigated, highly in foregut and skin physiological immune barrier. The transcripts of CiTRIF were significantly and rapidly induced in spleen and head kidney tissues at early stage post grass carp reovirus (GCRV) challenge. The modulations are significant but mild in CIK (C. idella kidney) cells post GCRV infection or poly(I:C) stimulation. The over-expression vector was constructed and transfected into CIK cell line to get stably expressing recombinant proteins. In CiTRIF transfected cells, mRNA expressions of CiTRIF, CiRIG-I, CiIRF7 and CiIFN-I were up-regulated. After GCRV infection, the transcripts of CiTRIF, CiRIG-I, CiIRF7 and CiIFN-I fell a little bit after a rapidly and strongly rise. In CiTRIF over-expression cells, virus load and titer were significantly lower than those in controls post GCRV challenge, and virus replication was inhibited obviously. The results indicate that the novel TRIF gene from grass carp plays important roles in modulating antiviral innate immune responses, and serve the further functional studies on TRIF gene in teleosts and immune evolution.
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Affiliation(s)
- Chunrong Yang
- College of Veterinary Medicine, Northwest A&F University, Yangling 712100, China
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Lu J, Yi L, Ke C, Zhang Y, Liu R, Chen J, Kung HF, He ML. The interaction between human enteroviruses and type I IFN signaling pathway. Crit Rev Microbiol 2013; 41:201-7. [PMID: 23919297 DOI: 10.3109/1040841x.2013.813903] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Human enteroviruses (HEV), very common and important human pathogens, cause infections in diverse ways. Recently, the large epidemic of HFMD caused by HEV infection became a growing threat to public health in China. As the first line of immune response, the type I interferon (IFN-α/β) pathway plays an essential role in antiviral infection, particularly in limiting both the early and late stages of infection. Because of co-evolution with the host, the viruses have evolved multiple strategies to evade or subvert the host immunity to ensure their survival. In this paper, we systematically reviewed and summarized the interaction between HEV infections and host type I IFN responses. We firstly described the recent findings of HEV recognition and IFN induction, specifically on host pattern-recognition receptors (PRRs) in HEV infection. Then we discussed the antiviral effect of IFN in HEV infection. Finally, we timely summarized the mechanisms of HEV to circumvent the IFN responses. Clarification of the complexity in this battle may provide us new strategies for prevention and antiviral treatment.
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Affiliation(s)
- Jing Lu
- Center for Diseases Control and Prevention of Guangdong Province , Guangzhou , China
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Harris KG, Coyne CB. Enter at your own risk: how enteroviruses navigate the dangerous world of pattern recognition receptor signaling. Cytokine 2013; 63:230-6. [PMID: 23764548 DOI: 10.1016/j.cyto.2013.05.007] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2013] [Accepted: 05/09/2013] [Indexed: 12/25/2022]
Abstract
Enteroviruses are the most common human viral pathogens worldwide. This genus of small, non-enveloped, single stranded RNA viruses includes coxsackievirus, rhinovirus, echovirus, and poliovirus species. Infection with these viruses can induce mild symptoms that resemble the common cold, but can also be associated with more severe syndromes such as poliomyelitis, neurological diseases including aseptic meningitis and encephalitis, myocarditis, and the onset of type I diabetes. In humans, polarized epithelial cells lining the respiratory and/or digestive tracts represent the initial sites of infection by enteroviruses. Control of infection in the host is initiated through the engagement of a variety of pattern recognition receptors (PRRs). PRRs act as the sentinels of the innate immune system and serve to alert the host to the presence of a viral invader. This review assembles the available data annotating the role of PRRs in the response to enteroviral infection as well as the myriad ways by which enteroviruses both interrupt and manipulate PRR signaling to enhance their own replication, thereby inducing human disease.
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Affiliation(s)
- Katharine G Harris
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, 427 Bridgeside Point II, 450 Technology Drive, Pittsburgh, PA 15219, USA.
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Antoniak S, Owens AP, Baunacke M, Williams JC, Lee RD, Weithäuser A, Sheridan PA, Malz R, Luyendyk JP, Esserman DA, Trejo J, Kirchhofer D, Blaxall BC, Pawlinski R, Beck MA, Rauch U, Mackman N. PAR-1 contributes to the innate immune response during viral infection. J Clin Invest 2013; 123:1310-22. [PMID: 23391721 DOI: 10.1172/jci66125] [Citation(s) in RCA: 117] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2012] [Accepted: 12/10/2012] [Indexed: 01/25/2023] Open
Abstract
Coagulation is a host defense system that limits the spread of pathogens. Coagulation proteases, such as thrombin, also activate cells by cleaving PARs. In this study, we analyzed the role of PAR-1 in coxsackievirus B3-induced (CVB3-induced) myocarditis and influenza A infection. CVB3-infected Par1(-/-) mice expressed reduced levels of IFN-β and CXCL10 during the early phase of infection compared with Par1(+/+) mice that resulted in higher viral loads and cardiac injury at day 8 after infection. Inhibition of either tissue factor or thrombin in WT mice also significantly increased CVB3 levels in the heart and cardiac injury compared with controls. BM transplantation experiments demonstrated that PAR-1 in nonhematopoietic cells protected mice from CVB3 infection. Transgenic mice overexpressing PAR-1 in cardiomyocytes had reduced CVB3-induced myocarditis. We found that cooperative signaling between PAR-1 and TLR3 in mouse cardiac fibroblasts enhanced activation of p38 and induction of IFN-β and CXCL10 expression. Par1(-/-) mice also had decreased CXCL10 expression and increased viral levels in the lung after influenza A infection compared with Par1(+/+) mice. Our results indicate that the tissue factor/thrombin/PAR-1 pathway enhances IFN-β expression and contributes to the innate immune response during single-stranded RNA viral infection.
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Affiliation(s)
- Silvio Antoniak
- Department of Medicine, Division of Hematology and Oncology, UNC McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
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