Interleukin-17A is dispensable for myocarditis but essential for the progression to dilated cardiomyopathy

G. Christian Baldeviano, Jobert G. Barin, Monica V. Talor, Sachin Srinivasan, Djahida Bedja, Dongfeng Zheng, Kathleen Gabrielson, Yoichiro Iwakura, Noel R. Rose, Daniela Cihakova

Research output: Contribution to journalArticlepeer-review

Abstract

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)γ-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, TNFα, and IL-1β 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.

Original languageEnglish (US)
Pages (from-to)1646-1655
Number of pages10
JournalCirculation research
Volume106
Issue number10
DOIs
StatePublished - May 28 2010

Keywords

  • Autoimmunity
  • Dilated cardiomyopathy
  • IL-17A
  • Myocarditis
  • Th17

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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