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Interleukin-17A Is Dispensable for Myocarditis but Essential for the Progression to Dilated Cardiomyopathy

Rationale: One-third of myocarditis cases progresses to dilated cardiomyopathy (DCM), but the mechanisms controlling this process are largely unknown. CD4+ T helper (Th)17 cells have been implicated in the pathogenesis of autoimmune diseases, but the role of Th17-produced cytokines during inflammation-induced cardiac remodeling has not been previously studied. Objective: We examined the importance of interleukin (IL)-17A in the progression of myocarditis to DCM using a mouse model. Methods and Results: Immunization of mice with myocarditogenic peptide in complete Freund's adjuvant induced the infiltration of IL-17A–producing Th17 cells into the inflamed heart. Unexpectedly, IL-17A–deficient mice developed myocarditis with similar incidence and severity compared to wild-type mice. Additionally, IL-17A deficiency did not ameliorate the severe myocarditis of interferon (IFN)&ggr;-deficient mice, suggesting that IL-17A plays a minimal role during acute myocarditis. In contrast, IL-17A–deficient mice were protected from postmyocarditis remodeling and did not develop DCM. Flow cytometric and cytokine analysis revealed an important role for IL-17A in heart-specific upregulation of IL-6, TNF&agr;, and IL-1&bgr; and the recruitment of CD11b+ monocyte and Gr1+ granulocyte populations into the heart. Furthermore, IL-17A–deficient mice had reduced interstitial myocardial fibrosis, downregulated expression of matrix metalloproteinase-2 and -9 and decreased gelatinase activity. Treatment of BALB/c mice with anti–IL-17A monoclonal antibody administered after the onset of myocarditis abrogated myocarditis-induced cardiac fibrosis and preserved ventricular function. Conclusions: Our findings reveal a critical role for IL-17A in postmyocarditis cardiac remodeling and the progression to DCM. Targeting IL-17A may be an attractive therapy for patients with inflammatory dilated cardiomyopathy.