Eosinophils and IL-4 are essential drivers of inflammatory dilated cardiomyopathy (BA7P.160)

Abstract Inflammatory dilated cardiomyopathy (DCMi) is a major cause of heart failure in children and young adults, and patients often require a heart transplant. DCMi develops in up to 30% of myocarditis patients, but the mechanisms involved in disease progression are poorly understood. In wildtype (WT) BALB/cJ mice, experimental autoimmune myocarditis (EAM) progresses to DCMi with heart failure. Surprisingly, eosinophil-deficient ΔGATA1 mice developed myocarditis similar to WT mice, but were completely protected from DCMi. This indicates that eosinophils are crucial for progression of myocarditis to DCMi. Moreover, the level of eosinophilia correlated with DCMi severity. We used two models of eosinophilic myocarditis: mice expressing IL-5 under the CD3 promoter and IFNγ-IL-17A-double knockout mice. Both strains developed massive eosinophil infiltration in the heart and even more severe DCMi than WT mice. Recently, eosinophils were shown to affect several physiological processes through their production of IL-4. We therefore assessed IL-4 producing cell types in myocarditis using IL-4 reporter mice. Indeed, eosinophils were the major IL-4 expressing cell type in EAM. Additionally, IL-4-deficient mice developed myocarditis but were completely protected from DCMi, matching the phenotype of ΔGATA1 mice. In conclusion, eosinophils are required for progression of myocarditis to DCMi, drive severe DCMi when present in large numbers, and likely mediate this process through IL-4.