Abstract
Abstract Cardiac manifestations are a major cause of morbidity and mortality in patients with eosinophil-associated diseases. Eosinophils have been proposed to play a pathologic role in the heart. Nevertheless, the pathways that recruit eosinophils to the heart have not been described. In IFNγ−/− IL-17A−/− mice, induction of experimental autoimmune myocarditis results in a Th-2-driven, eosinophilic inflammation. IFNγ−/− IL-17A−/− mice had much higher expression of the eosinophil-attracting chemokines eotaxin-1 (Ccl11) and eotaxin-2 (Ccl24) in the heart than wildtype mice. Genetic ablation of the eotaxin receptor CCR3 resulted in a dramatic decrease in heart infiltrating eosinophils. Adoptive transfer experiments with CCR3+/+ or CCR3−/− eosinophils into eosinophil-deficient ΔdblGATA1 or IFNγ−/− IL-17A−/− ΔdblGATA1 recipients showed that two conditions have to be met for efficient eosinophil trafficking to the inflamed heart: high eotaxin expression in the heart and expression of CCR3 by eosinophils. We identified the source of cardiac eotaxins by RT-PCR of FACS sorted heart cells and by immunohistochemistry. Eotaxin-1 was mainly produced by cardiac fibroblasts with interstitial localization in the heart. In vitro culture of cardiac fibroblasts with IL-4 and IL-13 induced eotaxin-1 expression. In contrast, eotaxin-2 was expressed by multiple inflammatory cell types, located at inflammatory foci, and substantial expression was only found in mice lacking IFNγ and IL-17A during myocarditis. In conclusion, eosinophil trafficking to the heart is dependent on the eotaxin-CCR3 pathway in mice with eosinophilic myocarditis. Blockade of this pathway may be a useful therapeutic approach to prevent eosinophil-mediated heart damage.
Published Version
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