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Circ Res. 2010 May 28;106(10):1646-55. doi: 10.1161/CIRCRESAHA.109.213157. Epub 2010 Apr 8.

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

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  • 1Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

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)gamma-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, TNFalpha, and IL-1beta 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.

PMID:
20378858
[PubMed - indexed for MEDLINE]
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