Cardiac fibroblasts mediate IL-17A–driven inflammatory dilated cardiomyopathy

Wu, Lei; Ong, SuFey; Talor, Monica V.; Barin, Jobert G.; Baldeviano, G. Christian; Kass, David A.; Bedja, Djahida; Zhang, Hao; Sheikh, A; Margolick, Joseph B.; Iwakura, Yoichiro; Rose, Noel R.; Čiháková, Daniela

doi:10.1084/jem.20132126

Cited by 150 publications

(169 citation statements)

References 47 publications

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“…Because IL-17A has also been shown to increase in peripheral blood and tissues of obese patients (9,10), and to exacerbate inflammation (41), our results suggest that ASCs could contribute to obesity-mediated inflammation through deviation of the Th1 response toward the Th-17 pathway in AT and subsequent propagation of inflammation in the periphery. Our study reinforces the concept that obesederived ASCs induce peripheral inflammation through Th17 cell promotion (13,(42)(43)(44).…”

Section: Discussionsupporting

confidence: 89%

Adipose Tissue–Derived Stem Cells From Obese Subjects Contribute to Inflammation and Reduced Insulin Response in Adipocytes Through Differential Regulation of the Th1/Th17 Balance and Monocyte Activation

et al. 2015

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Obesity, through low-grade inflammation, can drive insulin resistance and type 2 diabetes. While infiltration of adipose tissue (AT) with mononuclear cells (MNCs) is well established in obesity, the functional consequences of these interactions are less understood. Herein, we cocultured human adipose-derived stem cells (ASCs) from obese individuals with MNCs and analyzed their reciprocal behavior. Presence of ASCs 1) enhanced interleukin (IL)-17A secretion by Th17 cells, 2) inhibited γ-interferon and tumor necrosis factor α secretion by Th1 cells, and 3) increased monocyte-mediated IL-1β secretion. IL-17A secretion also occurred in stromal vascular fractions issued from obese but not lean individuals. Th17 polarization mostly depended on physical contacts between ASCs and MNCs—with a contribution of intracellular adhesion molecule-1—and occurred through activation of the inflammasome and phosphatidylinositol 3-kinase pathways. ASCs favored STAT3 over STAT5 transcription factor binding on STAT binding sites within the IL-17A/F gene locus. Finally, conditioned media from activated ASC-MNC cocultures inhibited adipocyte differentiation mRNA markers and impaired insulin-mediated Akt phosphorylation and lipolysis inhibition. In conclusion, we report that obese- but not lean-derived ASCs induce Th17 promotion and monocyte activation. This proinflammatory environment, in turn, inhibits adipogenesis and adipocyte insulin response. The demonstration of an ASC-Th17-monocyte cell axis reveals a novel proinflammatory process taking place in AT during obesity and defines novel putative therapeutic targets.

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Section: Discussionsupporting

confidence: 89%

Adipose Tissue–Derived Stem Cells From Obese Subjects Contribute to Inflammation and Reduced Insulin Response in Adipocytes Through Differential Regulation of the Th1/Th17 Balance and Monocyte Activation

et al. 2015

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“…This interpretation is consistent with the observation that mice deficient in IL-17A or its receptor IL-17Rα develop severe EAM comparable to WT mice [7,44]. However, those mice lack the chronic phase characterized by fibrosis and impairment of cardiac function (termed DCM), which usually occurs in WT mice around days 40 to 70 [7,44]. Therefore, IL-17A is not essential for the early-stage inflammatory process of acute EAM [43,44].…”

Section: Discussionsupporting

confidence: 87%

“…Th17 differentiation and/or activity are instead restrained by IFN-γ production in the WT setting. This interpretation is consistent with the observation that mice deficient in IL-17A or its receptor IL-17Rα develop severe EAM comparable to WT mice [7,44]. However, those mice lack the chronic phase characterized by fibrosis and impairment of cardiac function (termed DCM), which usually occurs in WT mice around days 40 to 70 [7,44].…”

supporting

confidence: 89%

“…However, those mice lack the chronic phase characterized by fibrosis and impairment of cardiac function (termed DCM), which usually occurs in WT mice around days 40 to 70 [7,44]. Therefore, IL-17A is not essential for the early-stage inflammatory process of acute EAM [43,44]. Hence in the WT setting, IFN-γ may have an important part in the establishment of acute EAM while IL-17A has an essential role in profibrotic remodeling, chronicity, and progression to DCM.…”

mentioning

confidence: 99%

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Absence of nonhematopoietic MHC class II expression protects mice from experimental autoimmune myocarditis

et al. 2015

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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. Keywords: CD4 + T cells Experimental autoimmune myocarditis (EAM) Endothelial antigen presentation Interferon-γ MHC class IIAdditional supporting information may be found in the online version of this article at the publisher's web-site Correspondence: Prof. Hans Acha-Orbea e-mail: hans.acha-orbea@unil.ch C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2016. 46: 656-664 Immunomodulation 657 IntroductionInflammatory dilated cardiomyopathy is a common cause of heart failure in young patients and often results from myocarditis in predisposed individuals [1]. CD4 + T-cell-mediated experimental autoimmune myocarditis (EAM) is a model for inflammatory heart disease and is induced in mice either by immunization with α-myosin heavy chain (α-MyHC) derived peptides emulsified in CFA [2][3][4] or by vaccination with α-MyHC-loaded activated dendritic cells (DCs) [5]. Typically, both Th1 and Th17 cells are induced during the course of EAM. It is assumed that both of these subsets mediate myocarditis as mice deficient in either interleukin 17 (IL-17) or interferon γ (IFN-γ) develop cardiac pathology [6,7]. Remarkably, heart-specific autoimmune inflammation has been shown to be a consequence of impaired central tolerance induction to α-MyHC during T-cell development in mice and in humans [8]. CD4 + T-cell-orchestrated immune responses are driven by MHC class II (MHCII) mediated antigen presentation. MHCII is primarily expressed on professional APCs. Cardiac APCs were suggested to present cardiac myosin before the onset of cardiac pathology [9], and DCs, the major APC subset able to initiate primary immune responses, were shown to be critical for ...

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“…45e47 However, we have determined that cardiac fibroblasts are an active source of cytokines and chemokines and can control the types of immune cells infiltrating the heart during myocarditis. 48 Eotaxins are prominent modulators of eosinophil trafficking and accumulation. In EAM, the depletion of NK cells increased eotaxin expression in whole heart tissue ( Figure 7A) and isolated cardiac fibroblasts on day 21 of EAM ( Figure 7, AeC), as seen by qPCR.…”

Section: Ccl11 Is Involved But Not Required For the Control Of Eosinomentioning

confidence: 99%

Natural Killer Cells Limit Cardiac Inflammation and Fibrosis by Halting Eosinophil Infiltration

Ong

Ligons

Barin

et al. 2015

The American Journal of Pathology

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Myocarditis is a leading cause of sudden cardiac failure in young adults. Natural killer (NK) cells, a subset of the innate lymphoid cell compartment, are protective in viral myocarditis. Herein, we demonstrated that these protective qualities extend to suppressing autoimmune inflammation. Experimental autoimmune myocarditis (EAM) was initiated in BALB/c mice by immunization with myocarditogenic peptide. During EAM, activated cardiac NK cells secreted interferon γ, perforin, and granzyme B, and expressed CD69, tumor necrosis factor-related apoptosis-inducing ligand treatment, and CD27 on their cell surfaces. The depletion of NK cells during EAM with anti-asialo GM1 antibody significantly increased myocarditis severity, and was accompanied by elevated fibrosis and a 10-fold increase in the percentage of cardiac-infiltrating eosinophils. The resultant influx of eosinophils to the heart was directly responsible for the increased disease severity in the absence of NK cells, because treatment with polyclonal antibody asialogangloside GM-1 did not augment myocarditis severity in eosinophil-deficient ΔdoubleGATA1 mice. We demonstrate that NK cells limit eosinophilic infiltration both indirectly, through altering eosinophil-related chemokine production by cardiac fibroblasts, and directly, by inducing eosinophil apoptosis in vitro. Altogether, we define a new pathway of eosinophilic regulation through interactions with NK cells.

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Cardiac fibroblasts mediate IL-17A–driven inflammatory dilated cardiomyopathy

Abstract: IL-17A stimulates cardiac fibroblasts to produce inflammatory mediators critical for the recruitment and differentiation of myeloid cells during inflammatory dilated cardiomyopathy.

Cited by 150 publications

References 47 publications

Adipose Tissue–Derived Stem Cells From Obese Subjects Contribute to Inflammation and Reduced Insulin Response in Adipocytes Through Differential Regulation of the Th1/Th17 Balance and Monocyte Activation

Adipose Tissue–Derived Stem Cells From Obese Subjects Contribute to Inflammation and Reduced Insulin Response in Adipocytes Through Differential Regulation of the Th1/Th17 Balance and Monocyte Activation

Absence of nonhematopoietic MHC class II expression protects mice from experimental autoimmune myocarditis

Natural Killer Cells Limit Cardiac Inflammation and Fibrosis by Halting Eosinophil Infiltration

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