Interleukin-17A is dispensable for myocarditis but essential for the progression to dilated cardiomyopathy (135.25)

Abstract

Abstract A third of myocarditis cases progress to dilated cardiomyopathy (DCM); however, the mechanisms controlling this process are largely unknown. Immunization of BALB/c mice with myocarditogenic peptide in CFA adjuvant induced the infiltration of pathogenic IL-17A-secreting T helper type-17 cells into the inflamed heart during the acute stage; and mild-to-severe DCM in the chronic stage of the disease. However, IL-17A deficiency did not abrogate the incidence or severity of myosin-induced myocarditis, nor did it ameliorate the severe disease of IFNγ-deficient mice, suggesting that IL-17A plays a minimal role during acute myocarditis. In contrast, during the chronic stage, IL-17A-deficient mice but not WT littermates were fully protected from the progression to DCM. Flow cytometry and cytokine analysis revealed an important role for IL-17A in the upregulation of IL-6, TNFα, and IL-1β in the heart tissue, and the recruitment of CD11b+ monocytes and Gr1+ granulocytes into the heart. These differences were associated with a significant decrease in myocardial fibrosis and dysregulation of matrix metalloproteinases. Furthermore, neutralization of endogenous IL-17A after the onset of myocarditis decreased myocardial fibrosis and improved systolic function. Our findings reveal a critical role for IL-17A in adverse cardiac remodeling leading to end-stage DCM, and suggest that targeting IL-17A may be an attractive therapeutic strategy for patients with inflammatory DCM.