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And IL-17A Γ the Absence of IFN- Fatal Eosinophilic Myocarditis Develops In Fatal Eosinophilic Myocarditis Develops in the Absence of IFN- γ and IL-17A Jobert G. Barin, G. Christian Baldeviano, Monica V. Talor, Lei Wu, SuFey Ong, DeLisa Fairweather, Djahida Bedja, This information is current as Natalie R. Stickel, Jillian A. Fontes, Ashley B. Cardamone, of September 25, 2021. Dongfeng Zheng, Kathleen L. Gabrielson, Noel R. Rose and Daniela Ciháková J Immunol 2013; 191:4038-4047; Prepublished online 18 September 2013; Downloaded from doi: 10.4049/jimmunol.1301282 http://www.jimmunol.org/content/191/8/4038 Supplementary http://www.jimmunol.org/content/suppl/2013/09/18/jimmunol.130128 http://www.jimmunol.org/ Material 2.DC1 References This article cites 70 articles, 16 of which you can access for free at: http://www.jimmunol.org/content/191/8/4038.full#ref-list-1 Why The JI? Submit online. by guest on September 25, 2021 • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Fatal Eosinophilic Myocarditis Develops in the Absence of IFN-g and IL-17A Jobert G. Barin,*,†,‡ G. Christian Baldeviano,‡,x Monica V. Talor,† Lei Wu,‡ SuFey Ong,‡ DeLisa Fairweather,{ Djahida Bedja,‖ Natalie R. Stickel,# Jillian A. Fontes,‡ Ashley B. Cardamone,† Dongfeng Zheng,† Kathleen L. Gabrielson,‖ Noel R. Rose,*,†,‡ and Daniela Ciha ´kova´† CD4+ T cells play a central role in inflammatory heart disease, implicating a cytokine product associated with Th cell effector function as a necessary mediator of this pathophysiology. IFN-g–deficient mice developed severe experimental autoimmune myocarditis (EAM), in which mice are immunized with cardiac myosin peptide, whereas IL-17A–deficient mice were protected 2/2 2/2 from progression to dilated cardiomyopathy. We generated IFN-g IL-17A mice to assess whether IL-17 signaling was Downloaded from responsible for the severe EAM of IFN-g2/2 mice. Surprisingly, IFN-g2/2IL-17A2/2 mice developed a rapidly fatal EAM. Eosinophils constituted a third of infiltrating leukocytes, qualifying this disease as eosinophilic myocarditis. We found increased cardiac production of CCL11/eotaxin, as well as Th2 deviation, among heart-infiltrating CD4+ cells. Ablation of eosinophil development improved survival of IFN-g2/2IL-17A2/2 mice, demonstrating the necessity of eosinophils in fatal heart failure. The severe and rapidly fatal autoimmune inflammation that developed in the combined absence of IFN-g and IL-17A constitutes a novel model of eosinophilic heart disease in humans. This is also, to our knowledge, the first demonstration that eosinophils http://www.jimmunol.org/ have the capacity to act as necessary mediators of morbidity in an autoimmune process. The Journal of Immunology, 2013, 191: 4038–4047. yocarditis encompasses a diverse family of inflam- myocarditis, a variant associated with poor prognosis and rapidly matory heart diseases associated with a large variety of fatal outcomes (6–8). M infectious and pharmacologic causes (1, 2). We have Experimental autoimmune myocarditis (EAM) is a model of published extensively on myocarditis as a paradigm of post- human inflammatory heart disease in which animals are immunized infectious autoimmunity, in which autoaggressive responses repre- with cardiac Ags to recapitulate autoreactive responses following sent a critical intermediary in the development of lasting cardiologic viral clearance (9, 10). The disease is dependent on CD4+ T cells, by guest on September 25, 2021 sequelae, often culminating in inflammatory dilated cardiomyopa- implicating cytokine products of these cells as necessary signaling thy (DCM) and heart failure (3–5). Myocarditis can take several intermediaries in disease pathophysiology (11). phenotypic forms in humans, including necrotizing eosinophilic IL-17 has been described as a family of proinflammatory cyto- kines bridging innate and adaptive immunity (12). We recently reported a critical requirement for IL-17A in mediating profibrotic *Immunology Training Program, Johns Hopkins University School of Medicine, † remodeling in the heart during EAM and subsequent progression Baltimore, MD 21205; Department of Pathology, Johns Hopkins University School 2/2 of Medicine, Baltimore, MD 21205; ‡William H. Feinstone Department of Molecular to DCM; although IL-17A mice are protected from fibrosis, Microbiology and Immunology, Johns Hopkins University Bloomberg School of they are not protected from inflammatory myocarditis (13). The Public Health, Baltimore, MD 21205; xDepartment of Parasitology, U.S. Naval Med- { archetypal member of this family, IL-17A, elicits neutrophilic ical Research Unit Six (NAMRU-6), Lima, Peru; Department of Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health, responses in host defense to fungi and extracellular bacteria (14, Baltimore, MD 21205; ‖Department of Comparative Medicine, Johns Hopkins Uni- 15). IL-17 signaling pathways bear phylogenetic and signaling # versity School of Medicine, Baltimore, MD 21205; and Department of Hematology relationships to the TLR/IL-1 superfamily (16). Immunologically and Oncology, University of Freiburg, 79106 Freiburg, Germany relevant production of IL-17A has been identified in various cel- Received for publication May 16, 2013. Accepted for publication August 14, 2013. lular populations, including gd T cells, NK cells, and a subset of This work was supported by National Institutes of Health/National Heart, Lung, and + Blood Institute (NIH/NHLBI) Grants R01 HL67290 and R01 HL113008 and a grant- CD4 T cells, termed “Th17” cells (17, 18). Th17 differentiation in-aid from the American Heart Association (to N.R.R.), NIH/NHLBI Grant R01 is programmed by coordinate signaling from TGF-b,IL-6,and HL087033 (to D.F.), the Mary Renner Fellowship in Autoimmune Disease Research and IL-23, and is dependent on the transcription factor retinoic acid the O’Leary-Wilson Fellowship at Johns Hopkins Autoimmune Disease Research Center from the American Autoimmune-Related Disease Association (to J.G.B.), and the receptor–related orphan receptor g (19, 20). Michel Mirowski M.D. Discovery Foundation, the W.W. Smith Charitable Trust (heart The involvement of Th17 CD4+ cells in autoimmune disease research Grant H1103), and the Children’s Cardiomyopathy Foundation (to D.C.). continues to be an active area of investigation. The importance of Address correspondence and reprint requests to Dr. Daniela Ciha´kova´, Johns Hopkins the Th17 lineage was discovered, in part, by contrasting the roles University School of Medicine, Ross 648, 720 Rutland Avenue, Baltimore, MD 21205-2196. E-mail address: [email protected] of IL-23 and IL-12 in the pathogenesis of experimental autoim- The online version of this article contains supplemental material. mune encephalomyelitis (EAE) (21). Adoptive transfer experiments have shown that Th17-conditioned cells induced qualitatively dif- Abbreviations used in this article: CVB3, coxsackievirus B3; DCM, dilated cardio- myopathy; DKO, double-knockout; EAE, experimental autoimmune encephalomy- ferent, if not more severe, autoimmune disease than did Th1 cells elitis; EAM, experimental autoimmune myocarditis; EF, ejection fraction; FS, (22–24). fractional shortening; IVSD, interventricular septal wall thickness at end diastole; LV, left ventricular; LVESD, LV end-systolic dimension; LVPWTED, LV posterior wall Th17 lineage cells are thought to be responsible for the protective thickness at end diastole; WT, wild-type. effect of IFN-g inseveralanimalmodelsofautoimmunedisease www.jimmunol.org/cgi/doi/10.4049/jimmunol.1301282 The Journal of Immunology 4039 2 2 (25, 26). IFN-g / mice develop more severe EAM than do wild- mation of the percentage of area of myocardium infiltrated with inflam- type (WT) controls, and progress to fibrosis and DCM at later matory cells, fibrosis, and cardiomyocyte necrosis, determined from five timepoints (27–30). More severe disease may be elicited in IFN-g2/2 sections per heart according to the following scoring system: grade 0, no inflammation; grade 1, , 10% of the heart section is involved; grade 2, mice through unconstrained outgrowth of autoaggressive Th17 10–30%; grade 3, 30–50%; grade 4, 50–90%; grade 5, . 90% (9). Grading clones in vivo. Several investigators have reported increased Th17 was performed by a minimum of two independent, blinded investigators responses in association with severe disease in IFN-g2/2 mice, and averaged. consistent with this hypothesis (31–35). These findings led us to Flow cytometry investigate whether the protective effect of IFN-g in EAM is mediated through suppressing Th17 differentiation in autoag- Heart-infiltrating leukocytes were isolated from animals perfused for 3 gressive CD4+ T cells. 3 min with 1 PBS + 0.5% BSA and digested in gentleMACS C Tubes according to the manufacturer’s instructions (Miltenyi Biotec). Spleno- Unexpectedly, we found that mice deficient in
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