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Ye J, Xu S, Liu X, Zhang Q, Li X, Zhang H, Ma J, Leng L, Zhang S. Effect and mechanism of T lymphocytes on human induced pluripotent stem cell-derived cardiomyocytes via Proteomics. Stem Cell Res Ther 2024; 15:236. [PMID: 39075540 PMCID: PMC11288085 DOI: 10.1186/s13287-024-03791-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Accepted: 06/08/2024] [Indexed: 07/31/2024] Open
Abstract
BACKGROUND Abnormalities in T cell activation play an important role in the pathogenesis of myocarditis, and persistent T cell responses can lead to autoimmunity and chronic cardiac inflammation, as well as even dilated cardiomyopathy. Although previous work has examined the role of T cells in myocarditis in animal models, the specific mechanism for human cardiomyocytes has not been investigated. METHODS In this study, we constructed the human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and established the T cell-mediated cardiac injury model by co-culturing with activated CD4 + T or CD8 + T cells that were isolated from peripheral mononuclear blood to elucidate the pathogenesis of myocardial cell injury caused by inflammation. RESULTS By combination of quantitative proteomics with tissue and cell immunofluorescence examination, we established a proteome profile of inflammatory myocardia from hiPSC-CMs with obvious cardiomyocyte injury and increased levels of lactate dehydrogenase content, creatine kinase isoenzyme MB and cardiac troponin. A series of molecular dysfunctions of hiPSC-CMs was observed and indicated that CD4 + cells could produce direct cardiomyocyte injury by activating the NOD-like receptor signals pathway. CONCLUSIONS The data presented in our study established a proteome map of inflammatory myocardial based on hiPSC-CMs injury model. These results can provide guidance in the discovery of improved clinical treatments for myocarditis.
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Affiliation(s)
- Jin Ye
- Stem cell and Regenerative Medicine Lab, Institute of Clinical Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Translational Medicine Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
- Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Sichi Xu
- Stem cell and Regenerative Medicine Lab, Institute of Clinical Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Translational Medicine Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
- Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Xiaoqing Liu
- Stem cell and Regenerative Medicine Lab, Institute of Clinical Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Translational Medicine Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
- State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
- College of Life Sciences, Hebei University, Baoding, 071002, China
| | - Qiyu Zhang
- Stem cell and Regenerative Medicine Lab, Institute of Clinical Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Translational Medicine Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Xiao Li
- State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
| | - Hui Zhang
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Jie Ma
- State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China.
| | - Ling Leng
- Stem cell and Regenerative Medicine Lab, Institute of Clinical Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Translational Medicine Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
| | - Shuyang Zhang
- Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
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Tran DT, Batchu SN, Advani A. Interferons and interferon-related pathways in heart disease. Front Cardiovasc Med 2024; 11:1357343. [PMID: 38665231 PMCID: PMC11043610 DOI: 10.3389/fcvm.2024.1357343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Accepted: 04/01/2024] [Indexed: 04/28/2024] Open
Abstract
Interferons (IFNs) and IFN-related pathways play key roles in the defence against microbial infection. However, these processes may also be activated during the pathogenesis of non-infectious diseases, where they may contribute to organ injury, or function in a compensatory manner. In this review, we explore the roles of IFNs and IFN-related pathways in heart disease. We consider the cardiac effects of type I IFNs and IFN-stimulated genes (ISGs); the emerging role of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway; the seemingly paradoxical effects of the type II IFN, IFN-γ; and the varied actions of the interferon regulatory factor (IRF) family of transcription factors. Recombinant IFNs and small molecule inhibitors of mediators of IFN receptor signaling are already employed in the clinic for the treatment of some autoimmune diseases, infections, and cancers. There has also been renewed interest in IFNs and IFN-related pathways because of their involvement in SARS-CoV-2 infection, and because of the relatively recent emergence of cGAS-STING as a pattern recognition receptor-activated pathway. Whether these advances will ultimately result in improvements in the care of those experiencing heart disease remains to be determined.
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Affiliation(s)
| | | | - Andrew Advani
- Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, ON, Canada
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3
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Smolgovsky S, Theall B, Wagner N, Alcaide P. Fibroblasts and immune cells: at the crossroad of organ inflammation and fibrosis. Am J Physiol Heart Circ Physiol 2024; 326:H303-H316. [PMID: 38038714 PMCID: PMC11219060 DOI: 10.1152/ajpheart.00545.2023] [Citation(s) in RCA: 16] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 11/13/2023] [Accepted: 11/27/2023] [Indexed: 12/02/2023]
Abstract
The immune and fibrotic responses have evolved to work in tandem to respond to pathogen clearance and promote tissue repair. However, excessive immune and fibrotic responses lead to chronic inflammation and fibrosis, respectively, both of which are key pathological drivers of organ pathophysiology. Fibroblasts and immune cells are central to these responses, and evidence of these two cell types communicating through soluble mediators or adopting functions from each other through direct contact is constantly emerging. Here, we review complex junctions of fibroblast-immune cell cross talk, such as immune cell modulation of fibroblast physiology and fibroblast acquisition of immune cell-like functions, as well as how these systems of communication contribute to organ pathophysiology. We review the concept of antigen presentation by fibroblasts among different organs with different regenerative capacities, and then focus on the inflammation-fibrosis axis in the heart in the complex syndrome of heart failure. We discuss the need to develop anti-inflammatory and antifibrotic therapies, so far unsuccessful to date, that target novel mechanisms that sit at the crossroads of the fibrotic and immune responses.
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Affiliation(s)
- Sasha Smolgovsky
- Department of Immunology, Tufts University School of Medicine, Boston, Massachusetts, United States
- Immunology Graduate Program, Graduate School of Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts, United States
| | - Brandon Theall
- Department of Immunology, Tufts University School of Medicine, Boston, Massachusetts, United States
- Immunology Graduate Program, Graduate School of Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts, United States
| | - Noah Wagner
- Department of Immunology, Tufts University School of Medicine, Boston, Massachusetts, United States
| | - Pilar Alcaide
- Department of Immunology, Tufts University School of Medicine, Boston, Massachusetts, United States
- Immunology Graduate Program, Graduate School of Biomedical Sciences, Tufts University School of Medicine, Boston, Massachusetts, United States
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Abstract
Viral infections are a leading cause of myocarditis and pericarditis worldwide, conditions that frequently coexist. Myocarditis and pericarditis were some of the early comorbidities associated with SARS-CoV-2 infection and COVID-19. Many epidemiologic studies have been conducted since that time concluding that SARS-CoV-2 increased the incidence of myocarditis/pericarditis at least 15× over pre-COVID levels although the condition remains rare. The incidence of myocarditis pre-COVID was reported at 1 to 10 cases/100 000 individuals and with COVID ranging from 150 to 4000 cases/100 000 individuals. Before COVID-19, some vaccines were reported to cause myocarditis and pericarditis in rare cases, but the use of novel mRNA platforms led to a higher number of reported cases than with previous platforms providing new insight into potential pathogenic mechanisms. The incidence of COVID-19 vaccine-associated myocarditis/pericarditis covers a large range depending on the vaccine platform, age, and sex examined. Importantly, the findings highlight that myocarditis occurs predominantly in male patients aged 12 to 40 years regardless of whether the cause was due to a virus-like SARS-CoV-2 or associated with a vaccine-a demographic that has been reported before COVID-19. This review discusses findings from COVID-19 and COVID-19 vaccine-associated myocarditis and pericarditis considering the known symptoms, diagnosis, management, treatment, and pathogenesis of disease that has been gleaned from clinical research and animal models. Sex differences in the immune response to COVID-19 are discussed, and theories for how mRNA vaccines could lead to myocarditis/pericarditis are proposed. Additionally, gaps in our understanding that need further research are raised.
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Affiliation(s)
- DeLisa Fairweather
- Department of Cardiovascular Medicine (D.F., D.J.B., D.N.D., L.T.C.), Mayo Clinic, Jacksonville, FL
- Department of Environmental Health Sciences and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD (D.F.,)
- Center for Clinical and Translational Science, Mayo Clinic, Rochester, MN (D.F., D.J.B., D.N.D.)
| | - Danielle J. Beetler
- Department of Cardiovascular Medicine (D.F., D.J.B., D.N.D., L.T.C.), Mayo Clinic, Jacksonville, FL
- Mayo Clinic Graduate School of Biomedical Sciences (D.J.B., D.N.D.), Mayo Clinic, Jacksonville, FL
- Center for Clinical and Translational Science, Mayo Clinic, Rochester, MN (D.F., D.J.B., D.N.D.)
| | - Damian N. Di Florio
- Department of Cardiovascular Medicine (D.F., D.J.B., D.N.D., L.T.C.), Mayo Clinic, Jacksonville, FL
- Mayo Clinic Graduate School of Biomedical Sciences (D.J.B., D.N.D.), Mayo Clinic, Jacksonville, FL
- Center for Clinical and Translational Science, Mayo Clinic, Rochester, MN (D.F., D.J.B., D.N.D.)
| | - Nicolas Musigk
- Deutsches Herzzentrum der Charité, Berlin, Germany (N.M., B.H.)
| | | | - Leslie T. Cooper
- Department of Cardiovascular Medicine (D.F., D.J.B., D.N.D., L.T.C.), Mayo Clinic, Jacksonville, FL
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Qiao W, Xiao YJ, Wang X, Sun LJ, Chen YX, Ren WD. A novel model of constrictive pericarditis associated with myocardial fibrosis in rats. Clin Exp Pharmacol Physiol 2021; 48:563-574. [PMID: 33349990 DOI: 10.1111/1440-1681.13449] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Accepted: 11/29/2020] [Indexed: 12/15/2022]
Abstract
An efficient animal model is fundamental for studies on the underlying mechanisms of constrictive pericarditis (CP). A novel CP rat model was established by pericardial injection composing of lipopolysaccharides (LPS) and talcum powder without thoracotomy. Pathological changes were confirmed by histological staining. E-flow Doppler of mitral valve, tissue Doppler E' in the medial mitral annular (E'sep ) and the lateral mitral annular (E'lat ) were measured to assess ventricular filling function. Circumferential, longitudinal, and radial strains (SC, SL and SR) and the respective strain rates (SrC, SrL and SrR) were analyzed in interventricular septum (IVS) and left ventricular free wall (LVFW). Rat cardiac fibroblasts (CFs) were treated with LPS. The activation of transforming growth factor β1 (TGF-β1) was confirmed by Q-PCR and western blot assays. Thickening of pericardium and fibrosis in pericardium and subepicardial myocardium were showed in the model group. Diastolic dysfunction in the CP group was indicated by decreased E'lat and E'lat /E'sep , increased E/E'lat , decreased EFW of SrC and SrL, increased AIVS and decreased E/A of SrC, SrL and SrR. Systolic dysfunction was indicated by decreased SCFW and SLFW in CP rats. The levels of TGF-β1, p-Smad2/3, α-smooth muscle actin (α-SMA), and collagen-I/III (COL-I/III) were increased in the CP group. The increased TGF-β1 that induced by LPS activated and phosphorylated Smad2/3 resulting in the secretion of α-SMA and COL-I/III. This model is of vital importance in studying the pathogenesis of CP.
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Affiliation(s)
- Wei Qiao
- Department of Ultrasound, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yang-Jie Xiao
- Department of Ultrasound, Shengjing Hospital of China Medical University, Shenyang, China
| | - Xin Wang
- Department of Ultrasound, Shengjing Hospital of China Medical University, Shenyang, China
| | - Li-Juan Sun
- Department of Ultrasound, Shengjing Hospital of China Medical University, Shenyang, China
- Department of Ultrasound, The First Hospital of Qinhuangdao, Qinhuangdao, China
| | - Yi-Xin Chen
- Department of Ultrasound, Shengjing Hospital of China Medical University, Shenyang, China
| | - Wei-Dong Ren
- Department of Ultrasound, Shengjing Hospital of China Medical University, Shenyang, China
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6
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Sun P, Wang N, Zhao P, Wang C, Li H, Chen Q, Mang G, Wang W, Fang S, Du G, Zhang M, Tian J. Circulating Exosomes Control CD4 + T Cell Immunometabolic Functions via the Transfer of miR-142 as a Novel Mediator in Myocarditis. Mol Ther 2020; 28:2605-2620. [PMID: 32882180 PMCID: PMC7704792 DOI: 10.1016/j.ymthe.2020.08.015] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 07/13/2020] [Accepted: 08/19/2020] [Indexed: 12/29/2022] Open
Abstract
CD4+ T cells undergo immunometabolic activation to mount an immunogenic response during experimental autoimmune myocarditis (EAM). Exosomes are considered key messengers mediating multiple T cell functions in autoimmune responses. However, the role of circulating exosomes in EAM immunopathogenesis and CD4+ T cell dysfunction remains elusive. Our objective was to elucidate the mechanism of action for circulating exosomes in EAM pathogenesis. We found that serum exosomes harvested from EAM mice induced CD4+ T cell immunometabolic dysfunction. Treatment with the exosome inhibitor GW4869 protected mice from developing EAM, underlying that exosomes are indispensable for the pathogenesis of EAM. Furthermore, by transfer of EAM exosomes, we confirmed that circulating exosomes initiate the T cell pathological immune response, driving the EAM pathological process. Mechanistically, EAM-circulating exosomes selectively loaded abundant microRNA (miR)-142. We confirmed methyl-CpG binding domain protein 2 (MBD2) and suppressor of cytokine signaling 1 (SOCS1) as functional target genes of miR-142. The miR-142/MBD2/MYC and miR-142/SOCS1 communication axes are critical to exosome-mediated immunometabolic turbulence. Moreover, the in vivo injection of the miR-142 inhibitor alleviated cardiac injury in EAM mice. This effect was abrogated by pretreatment with EAM exosomes. Collectively, our results indicate a newly endogenous mechanism whereby circulating exosomes regulate CD4+ T cell immunometabolic dysfunction and EAM pathogenesis via cargo miR-142.
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Affiliation(s)
- Ping Sun
- Department of Ultrasound, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China; The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, Heilongjiang Province, China
| | - Naixin Wang
- The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, Heilongjiang Province, China; Department of Cardiology, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China
| | - Peng Zhao
- Department of Ultrasound, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China
| | - Chao Wang
- Department of Ultrasound, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China; The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, Heilongjiang Province, China
| | - Hairu Li
- Department of Ultrasound, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China; The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, Heilongjiang Province, China
| | - Qi Chen
- The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, Heilongjiang Province, China; Department of Cardiology, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China
| | - Ge Mang
- The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, Heilongjiang Province, China; Department of Cardiology, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China
| | - Weiwei Wang
- The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, Heilongjiang Province, China; Department of Cardiology, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China
| | - Shaohong Fang
- The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, Heilongjiang Province, China
| | - Guoqing Du
- Department of Ultrasound, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China; The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, Heilongjiang Province, China
| | - Maomao Zhang
- The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, Heilongjiang Province, China; Department of Cardiology, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China.
| | - Jiawei Tian
- Department of Ultrasound, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China.
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7
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Wang X, Qiao W, Xiao Y, Sun L, Ren W. Experimental Research on the Evaluation of Left Ventricular Function by Layered Speckle Tracking in a Constrictive Pericarditis Rat Model. JOURNAL OF ULTRASOUND IN MEDICINE : OFFICIAL JOURNAL OF THE AMERICAN INSTITUTE OF ULTRASOUND IN MEDICINE 2020; 39:2219-2229. [PMID: 32395834 DOI: 10.1002/jum.15333] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Revised: 04/08/2020] [Accepted: 04/18/2020] [Indexed: 06/11/2023]
Abstract
OBJECTIVES In animal models with constrictive pericarditis (CP), detecting the function of cardiac systole by conventional noninvasive ultrasound is a challenge. We aimed to detect cardiac dysfunction in rat models with CP in the early stage by layered speckle tracking. METHODS We compared a rat CP model (n = 23, injected with a solution of 1-mg/mL lipopolysaccharides [0.5 mL] and a 10% talc suspension [0.5 mL]) with a control group (n = 20, no injection). After 8 weeks, conventional echocardiography and layered speckle tracking were used to assess the left ventricular structures and functions in the groups. RESULTS The global circumferential strain (CS) and longitudinal strain (LS) were decreased in the CP group (P < .05). The CS of the epicardial and middle layers in the CP group was decreased (P < .05), but the endocardial layer was not statistically different. The LS of the epicardial layer was decreased (P < .05), but the middle and endocardial layers were not statistically different. The global free-wall and septal-wall CS of the CP group was decreased (P < .05), mainly due to the decrease of CS of the epicardial and middle layers. The global free-wall LS of the CP group was decreased (P < .05), mainly due to the decrease of LS of the epicardial and middle layers. There were no significant differences between the groups in global LS of the septal wall. CONCLUSIONS In the early stage of CP, subepicardial myocardial damage precedes that of the subendocardial myocardium, and free-wall damage precedes that of the septal wall.
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Affiliation(s)
- Xin Wang
- Department of Ultrasound, Shengjing Hospital of China Medical University, Shenyang, China
| | - Wei Qiao
- Department of Ultrasound, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yangjie Xiao
- Department of Ultrasound, Shengjing Hospital of China Medical University, Shenyang, China
| | - Lijuan Sun
- Department of Ultrasound, Shengjing Hospital of China Medical University, Shenyang, China
- Department of Ultrasound, First Hospital of Qinhuangdao, Qinhuangdao, China
| | - Weidong Ren
- Department of Ultrasound, Shengjing Hospital of China Medical University, Shenyang, China
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8
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Ramasamy V, Mayosi BM, Sturrock ED, Ntsekhe M. Established and novel pathophysiological mechanisms of pericardial injury and constrictive pericarditis. World J Cardiol 2018; 10:87-96. [PMID: 30344956 PMCID: PMC6189073 DOI: 10.4330/wjc.v10.i9.87] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Revised: 04/06/2018] [Accepted: 04/22/2018] [Indexed: 02/06/2023] Open
Abstract
This review article aims to: (1) discern from the literature the immune and inflammatory processes occurring in the pericardium following injury; and (2) to delve into the molecular mechanisms which may play a role in the progression to constrictive pericarditis. Pericarditis arises as a result of a wide spectrum of pathologies of both infectious and non-infectious aetiology, which lead to various degrees of fibrogenesis. Current understanding of the sequence of molecular events leading to pathological manifestations of constrictive pericarditis is poor. The identification of key mechanisms and pathways common to most fibrotic events in the pericardium can aid in the design and development of novel interventions for the prevention and management of constriction. We have identified through this review various cellular events and signalling cascades which are likely to contribute to the pathological fibrotic phenotype. An initial classical pattern of inflammation arises as a result of insult to the pericardium and can exacerbate into an exaggerated or prolonged inflammatory state. Whilst the implication of major drivers of inflammation and fibrosis such as tumour necrosis factor and transforming growth factor β were foreseeable, the identification of pericardial deregulation of other mediators (basic fibroblast growth factor, galectin-3 and the tetrapeptide Ac-SDKP) provides important avenues for further research.
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Affiliation(s)
- Vinasha Ramasamy
- Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory 7925, South Africa
- Department of Integrative Biomedical Sciences, University of Cape Town, Observatory 7925, South Africa
| | - Bongani M Mayosi
- Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory 7925, South Africa
- Division of Cardiology, University of Cape Town, Observatory 7925, South Africa
| | - Edward D Sturrock
- Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory 7925, South Africa
- Department of Integrative Biomedical Sciences, University of Cape Town, Observatory 7925, South Africa
| | - Mpiko Ntsekhe
- Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory 7925, South Africa
- Division of Cardiology, University of Cape Town, Observatory 7925, South Africa
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9
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Nevers T, Salvador AM, Velazquez F, Ngwenyama N, Carrillo-Salinas FJ, Aronovitz M, Blanton RM, Alcaide P. Th1 effector T cells selectively orchestrate cardiac fibrosis in nonischemic heart failure. J Exp Med 2017; 214:3311-3329. [PMID: 28970239 PMCID: PMC5679176 DOI: 10.1084/jem.20161791] [Citation(s) in RCA: 164] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2016] [Revised: 06/13/2017] [Accepted: 08/21/2017] [Indexed: 12/20/2022] Open
Abstract
Despite emerging data indicating a role for T cells in profibrotic cardiac repair and healing after ischemia, little is known about whether T cells directly impact cardiac fibroblasts (CFBs) to promote cardiac fibrosis (CF) in nonischemic heart failure (HF). Recently, we reported increased T cell infiltration in the fibrotic myocardium of nonischemic HF patients, as well as the protection from CF and HF in TCR-α-/- mice. Here, we report that T cells activated in such a context are mainly IFN-γ+, adhere to CFB, and induce their transition into myofibroblasts. Th1 effector cells selectively drive CF both in vitro and in vivo, whereas adoptive transfer of Th1 cells, opposite to activated IFN-γ-/- Th cells, partially reconstituted CF and HF in TCR-α-/- recipient mice. Mechanistically, Th1 cells use integrin α4 to adhere to and induce TGF-β in CFB in an IFN-γ-dependent manner. Our findings identify a previously unrecognized role for Th1 cells as integrators of perivascular CF and cardiac dysfunction in nonischemic HF.
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Affiliation(s)
- Tania Nevers
- Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA
| | - Ane M Salvador
- Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA
| | - Francisco Velazquez
- Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA
| | - Njabulo Ngwenyama
- Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA
| | | | - Mark Aronovitz
- Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA
| | - Robert M Blanton
- Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA
| | - Pilar Alcaide
- Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA
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10
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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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11
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Types and predictors of interferon/ribavirin induced cardiac complications in the Egyptian patients with chronic hepatitis C virus. ACTA ACUST UNITED AC 2016. [DOI: 10.1016/j.jicc.2016.01.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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12
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Thelemann C, Haller S, Blyszczuk P, Kania G, Rosa M, Eriksson U, Rotman S, Reith W, Acha-Orbea H. Absence of nonhematopoietic MHC class II expression protects mice from experimental autoimmune myocarditis. Eur J Immunol 2015; 46:656-64. [PMID: 26621778 DOI: 10.1002/eji.201545945] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2015] [Revised: 10/26/2015] [Accepted: 11/25/2015] [Indexed: 01/14/2023]
Abstract
Experimental autoimmune myocarditis (EAM) is a CD4(+) T-cell-mediated model of human inflammatory dilated cardiomyopathies. Heart-specific CD4(+) T-cell activation is dependent on autoantigens presented by MHC class II (MHCII) molecules expressed on professional APCs. In this study, we addressed the role of inflammation-induced MHCII expression by cardiac nonhematopoietic cells on EAM development. EAM was induced in susceptible mice lacking inducible expression of MHCII molecules on all nonhematopoietic cells (pIV-/- K14 class II transactivator (CIITA) transgenic (Tg) mice) by immunization with α-myosin heavy chain peptide in CFA. Lack of inducible nonhematopoietic MHCII expression in pIV-/- K14 CIITA Tg mice conferred EAM resistance. In contrast, cardiac pathology was induced in WT and heterozygous mice, and correlated with elevated cardiac endothelial MHCII expression. Control mice with myocarditis displayed an increase in infiltrating CD4(+) T cells and in expression of IFN-γ, which is the major driver of nonhematopoietic MHCII expression. Mechanistically, IFN-γ neutralization in WT mice shortly before disease onset resulted in reduced cardiac MHCII expression and pathology. These findings reveal a previously overlooked contribution of IFN-γ to induce endothelial MHCII expression in the heart and to progress cardiac pathology during myocarditis.
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Affiliation(s)
- Christoph Thelemann
- Department of Biochemistry, CIIL, University of Lausanne, Epalinges, Switzerland
| | - Sergio Haller
- Department of Biochemistry, CIIL, University of Lausanne, Epalinges, Switzerland
| | - Przemyslaw Blyszczuk
- Division of Cardioimmunology, Centre of Molecular Cardiology, University of Zurich, Schlieren, Switzerland
| | - Gabriela Kania
- Research of Systemic Autoimmune Diseases, Division of Rheumatology, University Hospital Zürich, Schlieren, Switzerland
| | - Muriel Rosa
- Department of Biochemistry, CIIL, University of Lausanne, Epalinges, Switzerland
| | - Urs Eriksson
- Division of Cardioimmunology, Centre of Molecular Cardiology, University of Zurich, Schlieren, Switzerland
| | - Samuel Rotman
- Institute of Pathology, CHUV, University of Lausanne, Lausanne, Switzerland
| | - Walter Reith
- Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland
| | - Hans Acha-Orbea
- Department of Biochemistry, CIIL, University of Lausanne, Epalinges, Switzerland
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13
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Barin JG, Čiháková D. Control of inflammatory heart disease by CD4+ T cells. Ann N Y Acad Sci 2013; 1285:80-96. [PMID: 23692566 DOI: 10.1111/nyas.12134] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
This review focuses on autoimmune myocarditis and its sequela, inflammatory dilated cardiomyopathy (DCMI), and the inflammatory and immune mechanisms underlying the pathogenesis of these diseases. Several mouse models of myocarditis and DCMI have improved our knowledge of the pathogenesis of these diseases, informing more general problems of cardiac remodeling and heart failure. CD4(+) T cells are critical in driving the pathogenesis of myocarditis. We discuss in detail the role of T helper cell subtypes in the pathogenesis of myocarditis, the biology of T cell-derived effector cytokines, and the participation of other leukocytic effectors in mediating disease pathophysiology. We discuss interactions between these subsets in both suppressive and collaborative fashions. These findings indicate that cardiac inflammatory disease, and autoimmunity in general, may be more diverse in divergent effector mechanisms than has previously been appreciated.
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Affiliation(s)
- Jobert G Barin
- Department of Pathology, Division of Immunology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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14
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Abston ED, Coronado MJ, Bucek A, Onyimba JA, Brandt JE, Frisancho JA, Kim E, Bedja D, Sung YK, Radtke AJ, Gabrielson KL, Mitzner W, Fairweather D. TLR3 deficiency induces chronic inflammatory cardiomyopathy in resistant mice following coxsackievirus B3 infection: role for IL-4. Am J Physiol Regul Integr Comp Physiol 2012; 304:R267-77. [PMID: 23255589 DOI: 10.1152/ajpregu.00516.2011] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Recent findings indicate that TLR3 polymorphisms increase susceptibility to enteroviral myocarditis and inflammatory dilated cardiomyopathy (iDCM) in patients. TLR3 signaling has been found to inhibit coxsackievirus B3 (CVB3) replication and acute myocarditis in mouse models, but its role in the progression from myocarditis to iDCM has not been previously investigated. In this study we found that TLR3 deficiency increased acute (P = 5.9 × 10(-9)) and chronic (P = 6.0 × 10(-7)) myocarditis compared with WT B6.129, a mouse strain that is resistant to chronic myocarditis and iDCM. Using left ventricular in vivo hemodynamic assessment, we found that TLR3-deficient mice developed progressively worse chronic cardiomyopathy. TLR3 deficiency significantly increased viral replication in the heart during acute myocarditis from day 3 through day 12 after infection, but infectious virus was not detected in the heart during chronic disease. TLR3 deficiency increased cytokines associated with a T helper (Th)2 response, including IL-4 (P = 0.03), IL-10 (P = 0.008), IL-13 (P = 0.002), and TGF-β(1) (P = 0.005), and induced a shift to an immunoregulatory phenotype in the heart. However, IL-4-deficient mice had improved heart function during acute CVB3 myocarditis by echocardiography and in vivo hemodynamic assessment compared with wild-type mice, indicating that IL-4 impairs cardiac function during myocarditis. IL-4 deficiency increased regulatory T-cell and macrophage populations, including FoxP3(+) T cells (P = 0.005) and Tim-3(+) macrophages (P = 0.004). Thus, TLR3 prevents the progression from myocarditis to iDCM following CVB3 infection by reducing acute viral replication and IL-4 levels in the heart.
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Affiliation(s)
- Eric D Abston
- Department of Environmental Health Sciences, Johns Hopkins University, Bloomberg School of Public Health and School of Medicine, Baltimore, MD 21205, USA
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15
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Chen P, Baldeviano GC, Ligons DL, Talor MV, Barin JG, Rose NR, Cihakova D. Susceptibility to autoimmune myocarditis is associated with intrinsic differences in CD4(+) T cells. Clin Exp Immunol 2012; 169:79-88. [PMID: 22774982 DOI: 10.1111/j.1365-2249.2012.04598.x] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
A.SW and B10.S mice share the same major histocompatibility complex (MHC) haplotype (H-2(s)). However, A.SW mice are susceptible to experimental autoimmune myocarditis (EAM) and develop severe disease after immunization with myosin, whereas B10.S mice are resistant. We found that naive A.SW mice have intrinsically increased total CD4(+) T cell counts and increased proportions of CD4(+) T cells in their spleens compared to B10.S mice. Among total CD4(+) T cells, naive A.SW mice have a lower relative frequency of forkhead box protein 3 (FoxP3(+))CD25(+) regulatory T cells (T(regs)). A.SW mice also had a higher proportion of CD4(+) T cells and a lower proportion of T(regs) in their hearts and spleen during EAM, with greater T cell activation and proliferation, compared to B10.S mice. These differences in the T cell compartment were not antigen-specific, as ovalbumin/complete Freund's adjuvant (OVA/CFA) or CFA immunization elicited the same differences in CD4(+) T cells and T(regs) between A.SW and B10.S mice. Moreover, A.SW mice had more T helper type 17 (Th17) cells and B10.S had more Th1 cells in their hearts. The higher percentage of CD4(+) T cells and their enhanced potential to differentiate towards the Th17 pathway was also observed in naive A.SW mice. Interleukin (IL)-6 is required for Th17 induction. Interestingly, IL-6Rα expression was greater on naive A.SW CD4(+) T cells, compared to B10.S CD4(+) T cells, indicating that this intrinsic difference, together with a relatively lower T(reg) proportion of CD4(+) T cells, might lead to heightened Th17 responses and greater susceptibility to autoimmunity in A.SW mice.
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Affiliation(s)
- P Chen
- Department of Pathology, Division of Immunology, Johns Hopkins University School of Medicine, MD, USA
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16
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Abstract
PURPOSE OF REVIEW To present recent findings on the pathogenesis of coxsackievirus B3 (CVB3) myocarditis based on animal models, with a focus on the role of T helper (Th) immune responses in disease progression. RECENT FINDINGS Acute CVB3 myocarditis is known to be increased by Th1 immune responses, but recent findings indicate that Th1-type immunity protects against acute myocarditis by reducing viral replication and prevents the progression to chronic myocarditis and dilated cardiomyopathy (DCM) by inhibiting Th2 responses. Th2 responses reduce acute myocarditis by inhibiting Th1 responses via regulatory T cells and anti-inflammatory cytokines, but can be deleterious when they induce acute cardiac remodeling leading to chronic myocarditis/DCM. Th2-skewed immune responses allow resistant strains of mice to progress from myocarditis to DCM. In contrast, Th17 responses are elevated during acute and chronic myocarditis and have been found to contribute to cardiac remodeling and DCM. SUMMARY Recent data indicate that elevated Th2 and Th17 responses during acute CVB3 myocarditis are critical for the progression from myocarditis to DCM and heart failure because of their ability to induce cardiac remodeling. Th1 responses protect against CVB3 myocarditis by inhibiting Th2 responses and viral replication, but increase acute inflammation.
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Affiliation(s)
- DeLisa Fairweather
- Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
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17
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Li Y, Zhang C, Wu Y, Han Y, Cui W, Jia L, Cai L, Cheng J, Li H, Du J. Interleukin-12p35 Deletion Promotes CD4 T-Cell–Dependent Macrophage Differentiation and Enhances Angiotensin II–Induced Cardiac Fibrosis. Arterioscler Thromb Vasc Biol 2012; 32:1662-74. [DOI: 10.1161/atvbaha.112.249706] [Citation(s) in RCA: 89] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Objective—
Interleukin-12 is essential for the differentiation of naïve T cells into interferon-γ–producing T cells, which regulate inflammatory responses. We investigated this process of regulating hypertension-induced cardiac fibrosis.
Methods and Results—
Mice infused with angiotensin II showed a marked increase in interleukin-12p35 expression in cardiac macrophages. The degree of cardiac fibrosis was significantly enhanced in interleukin-12p35 knockout (p35-KO) mice compared with wild-type (WT) littermates in response to angiotensin II. Fibrotic hearts of p35-KO mice showed increased accumulation of alternatively activated (M2) macrophages and expression of M2 genes such as Arg-1 and Fizz1. Bone marrow–derived macrophages from WT or p35-KO mice did not differ in differentiation in response to angiotensin II treatment; however, in the presence of CD4
+
T cells, macrophages from p35-KO mice differentiated into M2 macrophages and showed elevated expression of transforming growth factor-β. Moreover, CD4
+
T-cell–treated p35-KO macrophages could stimulate cardiac fibroblasts to differentiate into α-smooth muscle actin–positive and collagen I–positive myofibroblasts in 3-dimensional nanofiber gels. Neutralizing antibodies against transforming growth factor-β inhibited myofibroblast formation induced by M2 macrophages.
Conclusion—
Deficiency in interleukin-12p35 regulates angiotensin II–induced cardiac fibrosis by promoting CD4
+
T-cell–dependent differentiation of M2 macrophages and production of transforming growth factor-β.
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Affiliation(s)
- Yulin Li
- From the Beijing AnZhen Hospital, Capital Medical University, The Key Laboratory of Remodeling-related Cardiovascular Diseases, Ministry of Education, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, China (Y.L., C.Z., Y.W., Y.H., W.C., L.J., L.C., J.C., J.D.); and Department of Pathology, Capital Medical University, Beijing, China (H.L.)
| | - Congcong Zhang
- From the Beijing AnZhen Hospital, Capital Medical University, The Key Laboratory of Remodeling-related Cardiovascular Diseases, Ministry of Education, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, China (Y.L., C.Z., Y.W., Y.H., W.C., L.J., L.C., J.C., J.D.); and Department of Pathology, Capital Medical University, Beijing, China (H.L.)
| | - Yina Wu
- From the Beijing AnZhen Hospital, Capital Medical University, The Key Laboratory of Remodeling-related Cardiovascular Diseases, Ministry of Education, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, China (Y.L., C.Z., Y.W., Y.H., W.C., L.J., L.C., J.C., J.D.); and Department of Pathology, Capital Medical University, Beijing, China (H.L.)
| | - Yalei Han
- From the Beijing AnZhen Hospital, Capital Medical University, The Key Laboratory of Remodeling-related Cardiovascular Diseases, Ministry of Education, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, China (Y.L., C.Z., Y.W., Y.H., W.C., L.J., L.C., J.C., J.D.); and Department of Pathology, Capital Medical University, Beijing, China (H.L.)
| | - Wei Cui
- From the Beijing AnZhen Hospital, Capital Medical University, The Key Laboratory of Remodeling-related Cardiovascular Diseases, Ministry of Education, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, China (Y.L., C.Z., Y.W., Y.H., W.C., L.J., L.C., J.C., J.D.); and Department of Pathology, Capital Medical University, Beijing, China (H.L.)
| | - Lixin Jia
- From the Beijing AnZhen Hospital, Capital Medical University, The Key Laboratory of Remodeling-related Cardiovascular Diseases, Ministry of Education, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, China (Y.L., C.Z., Y.W., Y.H., W.C., L.J., L.C., J.C., J.D.); and Department of Pathology, Capital Medical University, Beijing, China (H.L.)
| | - Lun Cai
- From the Beijing AnZhen Hospital, Capital Medical University, The Key Laboratory of Remodeling-related Cardiovascular Diseases, Ministry of Education, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, China (Y.L., C.Z., Y.W., Y.H., W.C., L.J., L.C., J.C., J.D.); and Department of Pathology, Capital Medical University, Beijing, China (H.L.)
| | - Jizhong Cheng
- From the Beijing AnZhen Hospital, Capital Medical University, The Key Laboratory of Remodeling-related Cardiovascular Diseases, Ministry of Education, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, China (Y.L., C.Z., Y.W., Y.H., W.C., L.J., L.C., J.C., J.D.); and Department of Pathology, Capital Medical University, Beijing, China (H.L.)
| | - Huihua Li
- From the Beijing AnZhen Hospital, Capital Medical University, The Key Laboratory of Remodeling-related Cardiovascular Diseases, Ministry of Education, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, China (Y.L., C.Z., Y.W., Y.H., W.C., L.J., L.C., J.C., J.D.); and Department of Pathology, Capital Medical University, Beijing, China (H.L.)
| | - Jie Du
- From the Beijing AnZhen Hospital, Capital Medical University, The Key Laboratory of Remodeling-related Cardiovascular Diseases, Ministry of Education, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing, China (Y.L., C.Z., Y.W., Y.H., W.C., L.J., L.C., J.C., J.D.); and Department of Pathology, Capital Medical University, Beijing, China (H.L.)
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18
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Abston ED, Barin JG, Cihakova D, Bucek A, Coronado MJ, Brandt JE, Bedja D, Kim JB, Georgakopoulos D, Gabrielson KL, Mitzner W, Fairweather D. IL-33 independently induces eosinophilic pericarditis and cardiac dilation: ST2 improves cardiac function. Circ Heart Fail 2012; 5:366-75. [PMID: 22454393 DOI: 10.1161/circheartfailure.111.963769] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND IL-33 through its receptor ST2 protects the heart from myocardial infarct and hypertrophy in animal models but, paradoxically, increases autoimmune disease. In this study, we examined the effect of IL-33 or ST2 administration on autoimmune heart disease. METHODS AND RESULTS We used pressure-volume relationships and isoproterenol challenge to assess the effect of recombinant (r) IL-33 or rST2 (eg, soluble ST2) administration on the development of autoimmune coxsackievirus B3 myocarditis and dilated cardiomyopathy in male BALB/c mice. The rIL-33 treatment significantly increased acute perimyocarditis (P=0.006) and eosinophilia (P=1.3×10(-5)), impaired cardiac function (maximum ventricular power, P=0.0002), and increased ventricular dilation (end-diastolic volume, P=0.01). The rST2 treatment prevented eosinophilia and improved heart function compared with rIL-33 treatment (ejection fraction, P=0.009). Neither treatment altered viral replication. The rIL-33 treatment increased IL-4, IL-33, IL-1β, and IL-6 levels in the heart during acute myocarditis. To determine whether IL-33 altered cardiac function on its own, we administered rIL-33 to undiseased mice and found that rIL-33 induced eosinophilic pericarditis and adversely affected heart function. We used cytokine knockout mice to determine that this effect was due to IL-33-mediated signaling but not to IL-1β or IL-6. CONCLUSIONS We show for the first time to our knowledge that IL-33 induces eosinophilic pericarditis, whereas soluble ST2 prevents eosinophilia and improves systolic function, and that IL-33 independently adversely affects heart function through the IL-33 receptor.
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Affiliation(s)
- Eric D Abston
- Department of Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health and School of Medicine, Baltimore, MD 21205, USA
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19
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N-3 polyunsaturated fatty acid supplementation does not reduce vulnerability to atrial fibrillation in remodeling atria. Heart Rhythm 2012; 9:1115-1122.e4. [PMID: 22342864 DOI: 10.1016/j.hrthm.2012.02.013] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2011] [Indexed: 11/24/2022]
Abstract
BACKGROUND Prophylactic supplementation with omega-3 polyunsaturated fatty acids (PUFAs) reduce vulnerability to atrial fibrillation (AF). The effect of PUFAs given after cardiac injury has occurred is unknown. OBJECTIVE To investigate using a model of pacing-induced cardiac injury, the time course of development of injury and whether it was altered by postinjury PUFAs. METHODS Sixty-five dogs were randomized to undergo simultaneous atrial and ventricular pacing (SAVP, 220 beats/min) for 0, 2, 7, or 14 days. Twenty-two dogs received PUFAs (850 mg/d) either prophylactically or after some pacing had occurred (postinjury). Electrophysiologic and echocardiographic measurements were taken at baseline and sacrifice. Atrial tissue samples were collected at sacrifice for histologic and molecular analyses. RESULTS With no PUFAs, the inducibility of AF increased with pacing duration (P < .001). Postinjury PUFAs (started after 7 days of pacing) did not reduce the inducibility of AF after 14 days of pacing (9.3% ± 8.8% no PUFAs vs 9.7% ± 9.9% postinjury PUFAs; P = .91). Atrial myocyte size and fibrosis increased with pacing duration (P < .05). Postinjury PUFAs did not significantly attenuate the cell size increase after 14 days of pacing (no PUFAs 38% ± 30% vs postinjury PUFAs 19% ± 28%; P = .11). Similarly, postinjury PUFAs did not attenuate the increase in fibrosis after 14 days of pacing (no PUFAs 66% ± 51% vs postinjury PUFAs 63% ± 76%; P = .90). CONCLUSION PUFA supplementation begun after cardiac injury has already occurred does not reduce atrial structural remodeling or vulnerability to AF.
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20
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Th2 regulation of viral myocarditis in mice: different roles for TLR3 versus TRIF in progression to chronic disease. Clin Dev Immunol 2011; 2012:129486. [PMID: 22013485 PMCID: PMC3195533 DOI: 10.1155/2012/129486] [Citation(s) in RCA: 75] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2011] [Accepted: 07/18/2011] [Indexed: 11/17/2022]
Abstract
Viral infections are able to induce autoimmune inflammation in the heart. Here, we investigated the role of virus-activated Toll-like receptor (TLR)3 and its adaptor TRIF on the development of autoimmune coxsackievirus B3 (CVB3) myocarditis in mice. Although TLR3- or TRIF-deficient mice developed similarly worse acute CVB3 myocarditis and viral replication compared to control mice, disease was significantly worse in TRIF compared to TLR3-deficient mice. Interestingly, TLR3-deficient mice developed an interleukin (IL)-4-dominant T helper (Th)2 response during acute CVB3 myocarditis with elevated markers of alternative activation, while TRIF-deficient mice elevated the Th2-associated cytokine IL-33. Treatment of TLR3-deficient mice with recombinant IL-33 improved heart function indicating that elevated IL-33 in the context of a classic Th2-driven response protects against autoimmune heart disease. We show for the first time that TLR3 versus TRIF deficiency results in different Th2 responses that uniquely influence the progression to chronic myocarditis.
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21
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Pericardial constriction after lung transplantation. Ann Thorac Surg 2010; 90:1361-3. [PMID: 20868850 DOI: 10.1016/j.athoracsur.2010.03.027] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2010] [Revised: 02/13/2010] [Accepted: 03/17/2010] [Indexed: 11/24/2022]
Abstract
Pericardial constriction is extremely rare after lung transplantation. We present a case and review the potential contributing factors for pericardial constriction after lung transplantation. Treatment for this condition, irrespective of the cause, remains pericardiectomy.
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Barin JG, Talor MV, Baldeviano GC, Kimura M, Rose NR, Čiháková D. Mechanisms of IFNγ regulation of autoimmune myocarditis. Exp Mol Pathol 2010; 89:83-91. [PMID: 20599938 PMCID: PMC4266481 DOI: 10.1016/j.yexmp.2010.06.005] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2010] [Revised: 06/25/2010] [Accepted: 06/04/2010] [Indexed: 12/21/2022]
Abstract
A protective effect of interferon-gamma (IFNγ) has been described in a number of models of autoimmune disease, including experimental autoimmune myocarditis (EAM). Some reports have suggested that regulation of apoptosis in autoreactive lymphocytes mediate these protective functions. We examined the potential of IFNγ to regulate apoptotic mechanisms in detail, both in vitro and in vivo in EAM. We observed multiple apoptotic defects in caspase activity, and the expression of TNF superfamily members on CD4(+) T cells. In addition, we observed selective defects in CD4(+) T cell activation in response to antigenic stimulation. These activation and apoptotic defects were CD4(+) cell autonomous, independent of the genotype of APCs. Inhibition of nitric oxide production in vivo did not reproduce the severe form of EAM of IFNγ-deficient mice, indicating that this pathway does not mediate the protective effect of IFNγ. Crosswise adoptive transfer of wild type, IFNγ(-/-), and IFNγR(-/-)EAM demonstrated that IFNγ signaling was critical in CD4(+) cells, but that non-CD4(+) sources of IFNγ production were also involved in the control of disease. Together, these data indicate multiple mechanisms of autonomous and non-autonomous CD4(+) T cell regulation mediated by IFNγ in the control of autoimmune heart disease.
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Affiliation(s)
- Jobert G. Barin
- Training Program in Immunology, Johns Hopkins University School of Medicine
| | - Monica V. Talor
- Department of Pathology, Division of Immunology, Johns Hopkins University School of Medicine
| | - G. Christian Baldeviano
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health
| | - Miho Kimura
- Department of Pathology, Division of Immunology, Johns Hopkins University School of Medicine
| | - Noel R. Rose
- Training Program in Immunology, Johns Hopkins University School of Medicine
- Department of Pathology, Division of Immunology, Johns Hopkins University School of Medicine
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health
| | - Daniela Čiháková
- Department of Pathology, Division of Immunology, Johns Hopkins University School of Medicine
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Abstract
Macrophages are innate immune cells that play an important role in activation of the immune response and wound healing. Pathogens that require T helper-type 2 (Th2) responses for effective clearance, such as parasitic worms, are strong inducers of alternatively activated or M2 macrophages. However, infections such as bacteria and viruses that require Th1-type responses may induce M2 as a strategy to evade the immune system. M2 are particularly efficient at scavenging self tissues following injury through receptors like the mannose receptor and scavenger receptor-A. Thus, M2 may increase autoimmune disease by presenting self tissue to T cells. M2 may also exacerbate immune complex (IC)-mediated pathology and fibrosis, a hallmark of autoimmune disease in women, due to the release of profibrotic factors such as interleukin-1beta, transforming growth factor-beta, fibronectin and matrix metalloproteinases. We have found that M2 comprise anywhere from 30% to 70% of the infiltrate during acute viral or experimental autoimmune myocarditis, and shifts in M2 populations correlate with increased IC deposition, fibrosis and chronic autoimmune pathology. Thus, women may be at an increased risk of M2-mediated autoimmunity due to estrogen's ability to increase Th2 responses.
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Affiliation(s)
- Delisa Fairweather
- Department of Environmental Health Sciences, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, MD 21205, USA.
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24
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Morton J, Coles B, Wright K, Gallimore A, Morrow JD, Terry ES, Anning PB, Morgan BP, Dioszeghy V, Kühn H, Chaitidis P, Hobbs AJ, Jones SA, O'Donnell VB. Circulating neutrophils maintain physiological blood pressure by suppressing bacteria and IFNgamma-dependent iNOS expression in the vasculature of healthy mice. Blood 2008; 111:5187-94. [PMID: 18281503 PMCID: PMC2602588 DOI: 10.1182/blood-2007-10-117283] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2007] [Accepted: 02/12/2008] [Indexed: 12/29/2022] Open
Abstract
Whether leukocytes exert an influence on vascular function in vivo is not known. Here, genetic and pharmacologic approaches show that the absence of neutrophils leads to acute blood pressure dysregulation. Following neutrophil depletion, systolic blood pressure falls significantly over 3 days (88.0 +/- 3.5 vs 104.0 +/- 2.8 mm Hg, day 3 vs day 0, mean +/- SEM, P < .001), and aortic rings from neutropenic mice do not constrict properly. The constriction defect is corrected using l-nitroarginine-methyl ester (L-NAME) or the specific inducible nitric oxide synthase (iNOS) inhibitor 1400W, while acetylcholine relaxation is normal. iNOS- or IFNgamma-deficient mice are protected from neutropenia-induced hypotension, indicating that iNOS-derived nitric oxide (NO) is responsible and that its induction involves IFNgamma. Oral enrofloxacin partially inhibited hypotension, implicating bacterial products. Roles for cyclooxygenase, complement C5, or endotoxin were excluded, although urinary prostacyclin metabolites were elevated. Neutrophil depletion required complement opsinization, with no evidence for intravascular degranulation. In summary, circulating neutrophils contribute to maintaining physiological tone in the vasculature, at least in part through suppressing early proinflammatory effects of infection. The speed with which hypotension developed provides insight into early changes that occur in the absence of neutrophils and illustrates the importance of constant surveillance of mucosal sites by granulocytes in healthy mice.
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Affiliation(s)
- Jonathan Morton
- Department of Medical Biochemistry & Immunology, Cardiff University, Cardiff, United Kingdom
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Cihakova D, Barin JG, Baldeviano GC, Kimura M, Talor MV, Zimmerman DH, Talor E, Rose NR. L.E.A.P.S. heteroconjugate is able to prevent and treat experimental autoimmune myocarditis by altering trafficking of autoaggressive cells to the heart. Int Immunopharmacol 2008; 8:624-33. [PMID: 18387504 PMCID: PMC2716547 DOI: 10.1016/j.intimp.2008.01.004] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2007] [Revised: 01/02/2008] [Accepted: 01/03/2008] [Indexed: 11/26/2022]
Abstract
We evaluated the efficacy of the Ligand Epitope Antigen Presentation System (L.E.A.P.S.trade mark) in preventing or treating experimental autoimmune myocarditis (EAM) in A/J mice. L.E.A.P.S. (here, J-My-1) is a conjugate of the myocarditogenic peptide of cardiac myosin MyHCalpha(334-352) (My-1) and J peptide, derived from the sequence of human beta-2 microglobulin. Remarkably, early prophylactic (J-My-1 injected on days -14 and -7 before EAM induction), late prophylactic (J-My-1 injected on days 0, 7, 14, and 21), and therapeutic (J-My-1 injected on days 7, 14, and 21 or 10, 17 and 24) administration of J-My-1 significantly decreased the incidence and severity of EAM. However, extended therapeutic treatment was associated with anaphylaxis and death, corresponding with global immune activation associated with J-My-1 treatment. In J-My1-treated animals, we observed expanded numbers of activated CD69+ and CD44+ CD4+ and CD8+ T cells in the spleens. J-My-1 treatment also increased the proportion of CD11c+ dendritic cells in spleens and induced strong production of anti-J-My-1 specific antibodies. J-My-1 injections resulted in decreased levels of chemokines MIP-1alpha and IP-10 in hearts. We propose that J-My-1 treatment interferes with trafficking of autoaggressive immune cells to the heart.
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Affiliation(s)
- Daniela Cihakova
- Department of Pathology, the Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. <>
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Cihakova D, Barin JG, Afanasyeva M, Kimura M, Fairweather D, Berg M, Talor MV, Baldeviano GC, Frisancho S, Gabrielson K, Bedja D, Rose NR. Interleukin-13 protects against experimental autoimmune myocarditis by regulating macrophage differentiation. THE AMERICAN JOURNAL OF PATHOLOGY 2008; 172:1195-208. [PMID: 18403598 PMCID: PMC2329830 DOI: 10.2353/ajpath.2008.070207] [Citation(s) in RCA: 117] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Accepted: 02/05/2008] [Indexed: 02/04/2023]
Abstract
We report here that interleukin (IL)-13 protects BALB/c mice from myocarditis, whether induced by peptide immunization or by viral infection. In contrast to mild disease in IL-4 knockout (KO) BALB/c mice, IL-13 KO BALB/c mice developed severe coxsackievirus B3 (CVB3)-induced autoimmune myocarditis and myocarditogenic peptide-induced experimental autoimmune myocarditis. Such severe disease was characterized by increased cardiac inflammation, increased total intracardiac CD45(+) leukocytes, elevated anti-cardiac myosin autoantibodies, and increased cardiac fibrosis. Echocardiography revealed that IL-13 KO mice developed severe dilated cardiomyopathy with impaired cardiac function and heart failure. Hearts of IL-13 KO mice had increased levels of the proinflammatory and profibrotic cytokines IL-1beta, IL-18, interferon-gamma, transforming growth factor-beta1, and IL-4 as well as histamine. The hallmark of the disease in IL-13 KO mice was the up-regulation of T-cell responses. CD4(+) T cells were increased in IL-13 KO hearts both proportionally and in absolute number. Splenic T cells from IL-13 KO mice were highly activated, and myosin stimulation additionally increased T-cell proliferation. CD4(+)CD25(+)Foxp3(+) regulatory T-cell numbers were decreased in the spleens of IL-13 KO mice. IL-13 deficiency led to decreased levels of alternatively activated CD206(+) and CD204(+) macrophages and increased levels of classically activated macrophages. IL-13 KO mice had increased caspase-1 activation, leading to increased production of both IL-1beta and IL-18. Therefore, IL-13 protects against myocarditis by modulating monocyte/macrophage populations and by regulating their function.
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Affiliation(s)
- Daniela Cihakova
- Johns Hopkins University, Department of Pathology, Division of Immunology, Ross 648, 720 Rutland Ave., Baltimore, MD 21205, USA.
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Fairweather D, Rose NR. Coxsackievirus-induced myocarditis in mice: a model of autoimmune disease for studying immunotoxicity. Methods 2007; 41:118-22. [PMID: 17161308 PMCID: PMC1764911 DOI: 10.1016/j.ymeth.2006.07.009] [Citation(s) in RCA: 159] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/19/2006] [Indexed: 11/18/2022] Open
Abstract
Excellent animal models are available for virus-induced and autoimmune heart disease that are remarkably similar to human disease. Developing good animal models for heart disease is crucial because cardiovascular disease is now the leading cause of death in the United States and is estimated to be the leading cause of death in the world by the year 2020. A significant proportion of heart disease in Western populations is associated with inflammation. Myocarditis, or inflammation of the heart muscle, is the major cause of sudden death in young adults. Although most individuals recover from acute myocarditis, genetically susceptible individuals may go on to develop chronic myocarditis and dilated cardiomyopathy (DCM) resulting in congestive heart failure. In this article, we describe a model of autoimmune myocarditis and DCM induced by inoculation with heart-passaged coxsackievirus B3 (CVB3). Intraperitoneal inoculation of susceptible mice with CVB3 induces acute cardiac inflammation from days 7 to 14 postinfection (pi) that progresses to chronic myocarditis and DCM from day 28 to at least 56 pi. The model of CVB3-induced myocarditis presented here allows dissection of the contribution of viral infection and xenobiotics on immune dysregulation and inflammation in the heart. An improved understanding of the interaction between environmental exposures and the development of heart disease represents a clear challenge for immunotoxicologists.
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Affiliation(s)
| | - Noel R. Rose
- Pathology, and
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University, Baltimore, MD 21205, USA
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Fairweather D, Frisancho-Kiss S, Njoku DB, Nyland JF, Kaya Z, Yusung SA, Davis SE, Frisancho JA, Barrett MA, Rose NR. Complement receptor 1 and 2 deficiency increases coxsackievirus B3-induced myocarditis, dilated cardiomyopathy, and heart failure by increasing macrophages, IL-1beta, and immune complex deposition in the heart. THE JOURNAL OF IMMUNOLOGY 2006; 176:3516-24. [PMID: 16517720 DOI: 10.4049/jimmunol.176.6.3516] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Complement and complement receptors (CR) play a central role in immune defense by initiating the rapid destruction of invading microorganisms, amplifying the innate and adaptive immune responses, and mediating solubilization and clearance of immune complexes. Defects in the expression of C or CR have been associated with loss of tolerance to self proteins and the development of immune complex-mediated autoimmune diseases such as systemic lupus erythematosus. In this study, we examined the role of CR on coxsackievirus B3 (CVB3)-induced myocarditis using mice deficient in CR1/2. We found that CR1/2 deficiency significantly increased acute CVB3 myocarditis and pericardial fibrosis resulting in early progression to dilated cardiomyopathy and heart failure. The increase in inflammation was not due to increased viral replication, which was not significantly altered in the hearts of CR1/2-deficient mice, but was associated with increased numbers of macrophages, IL-1beta levels, and immune complex deposition in the heart. The complement regulatory protein, CR1-related gene/protein Y (Crry), was increased on cardiac macrophage populations, while immature B220(low) B cells were increased in the spleen of CR1/2-deficient mice during acute CVB3-induced myocarditis. These results show that expression of CR1/2 is not necessary for effective clearance of CVB3 infection, but prevents immune-mediated damage to the heart.
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Affiliation(s)
- DeLisa Fairweather
- Department of Environmental Health Sciences, Johns Hopkins University and Bloomberg School of Public Health, 615 North Wolfe Street, Rm. E7628, Baltimore, MD 21205, USA.
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