Eosinophils promote myocarditis and dilated cardiomyopathy by enhancing Th17 responses (101.27)

Abstract

Abstract Eosinophilic myocarditis is a rare but potentially fatal form of myocarditis that is occasionally associated with systemic eosinophilia. It is not known how eosinophils localize to the myocardium or which are the mechanisms underlying their involvement in inflammatory heart diseases. Here, we assessed the role of eosinophils using a murine model of experimental autoimmune myocarditis (EAM). We have previously observed that eosinophils are recruited to the inflamed heart. Eosinophil-deficient mice (ΔdblGATA1) had decreased EAM and did not develop dilated cardiomyopathy (DCM) compared to wild-type BALB/c control mice. In contrast, IL-5 transgenic mice (IL-5Cd3) developed peripheral eosinophilia, severe EAM, increased myocardial fibrosis and accelerated DCM. Transfer of bone marrow-derived eosinophils increased EAM severity in ΔdblGATA1 mice, suggesting a direct pathogenic role for eosinophils in myocarditis. The trafficking of eosinophils to the heart was independent of IL-5 and CCR3 but partially dependent on the cytosolic phospholipase-2. Flow cytometry analysis revealed that the frequency of IL-17A-secreting T cells tracked with the number of eosinophils; it was significantly increased in IL-5Cd3 and decreased in ΔdblGATA1 mice. This study provides the first direct evidence for a pathogenic role in eosinophils in myocarditis and DCM. Additionally, our findings support the hypothesis that eosinophils may promote Th17 responses during myocarditis.