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

Wu, L;Ong, S;Talor, MV;Barin, JG;Baldeviano, GC;Kass, DA;Bedja, D;Zhang, H;Sheikh, A;Margolick, JB;Iwakura, Y;Rose, NR;Cihkov, D;

Inflammatory dilated cardiomyopathy (DCMi) is a major cause of heart failure in individuals below the age of 40. We recently reported that IL-17A is required for the development of DCMi. We show a novel pathway connecting IL-17A, cardiac fibroblasts (CFs), GM-CSF, and heart-infiltrating myeloid cells with the pathogenesis of DCMi. Il17ra(-/-) mice were protected from DCMi, and this was associated with significantly diminished neutrophil and Ly6Chi monocyte/macrophage (MO/M) cardiac infiltrates. Depletion of Ly6Chi MO/M also protected mice from DCMi. Mechanistically, IL-17A stimulated CFs to produce key chemokines and cytokines that are critical downstream effectors in the recruitment and differentiation of myeloid cells. Moreover, IL-17A directs Ly6Chi MO/M in trans toward a more proinflammatory phenotype via CF-derived GM-CSF. Collectively, this IL-17A-fibroblast-GM-CSF-MO/M axis could provide a novel target for the treatment of DCMi and related inflammatory cardiac diseases.