The pathogenic role of eosinophils in autoimmune myocarditis and inflammatory dilated cardiomyopathy
Diny, Nicola L
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Myocarditis is a rare but potentially devastating inflammatory disease of the heart. Severity can vary widely from asymptomatic to fulminant disease and sudden death. Up to 30% of myocarditis patients go on to develop inflammatory dilated cardiomyopathy (DCMi), which is a major cause of heart failure in children and young adults. Patients with eosinophilia frequently develop cardiomyopathy, suggesting a pathogenic role for eosinophils in the heart. We used the experimental autoimmune myocarditis (EAM) model in different genetically modified mice to determine the role of eosinophils in myocarditis and DCMi. Using adoptive transfer experiments and CCR3-/- mice, we found that the eotaxin-CCR3 pathway was required for eosinophil trafficking to the heart in mice with eosinophilic myocarditis. We identified cardiac fibroblasts as the source of eotaxin-1 and infiltrating macrophages as the source of eotaxin-2. Eotaxins were also increased in patients with eosinophilic myocarditis compared to chronic lymphocytic myocarditis and eotaxin expression was positively correlated with the number of heart-infiltrating eosinophils. We then showed that eosinophils contribute to myocarditis pathology. Eosinophils were dispensable for myocarditis induction but required for progression to DCMi. Eosinophil-deficient ΔdblGATA1 mice, in contrast to WT mice, showed no signs of heart failure by echocardiography. Induction of EAM in hypereosinophilic IL-5Tg mice resulted in eosinophilic myocarditis with severe atrial inflammation, which progressed to severe DCMi. This was not a direct effect of IL-5 as IL-5TgΔdblGATA1 mice were protected from DCMi while IL-5-/- mice exhibited DCMi comparable to WT mice. Eosinophils drove progression to DCMi through their production of IL-4. Our experiments showed eosinophils were the major IL-4 expressing cell type in the heart during EAM, IL-4-/- mice were protected from DCMi like ΔdblGATA1 mice, and eosinophil-specific IL-4 deletion resulted in improved heart function. In conclusion, eosinophils drive progression of myocarditis to DCMi, cause severe DCMi when present in large numbers, and mediate this process through IL-4.