Abstract
Two types of monocytes, Ly6Chi and Ly6Clo, infiltrate the heart in murine experimental autoimmune myocarditis (EAM). We discovered a previously unappreciated role for cardiac fibroblasts in facilitating both Ly6Chi and Ly6Clo monocyte-to-macrophage differentiation, allowing these macrophages to perform divergent functions in myocarditis progression. During the acute phase of EAM, IL-17A is highly abundant. It signals through cardiac fibroblasts to attenuate efferocytosis of Ly6Chi monocyte-derived macrophages and simultaneously prevents Ly6Clo monocyte-to-macrophage differentiation. We demonstrated an inverse correlation of cardiac IL-17A and efferocytic receptor expression in human heart failure. During the resolution of inflammation, Ly6Clo monocyte-to-macrophage differentiation is restored as IL-17A signaling through cardiac fibroblast subsides. Ly6Clo monocyte-derived macrophages exhibit robust MHC class II-associated antigen presentation but are incapable of engulfing debris. We propose that MHCII+ Ly6Clo monocyte-derived macrophages may prevent fibrosis and heart failure.
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