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The Cardiac Microenvironment Instructs Divergent Monocyte Fates and Functions in Myocarditis

Hou, X;Chen, G;Bracamonte-Baran, W;Choi, HS;Diny, NL;Sung, J;Hughes, D;Won, T;Wood, MK;Talor, MV;Hackam, DJ;Klingel, K;Davogustto, G;Taegtmeyer, H;Coppens, I;Barin, JG;ihkov, D;

Two types of monocytes, Ly6Chi and Ly6Clo, infiltrate the heart in murine experimental autoimmune myocarditis (EAM). We discovered a role for cardiac fibroblasts in facilitating monocyte-to-macrophage differentiation of both Ly6Chi and Ly6Clo cells, 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 (MDMs) and simultaneously prevents Ly6Clo monocyte-to-macrophage differentiation. We demonstrated an inverse clinical correlation between heart IL-17A levels and efferocytic receptor expressions in humans with heart failure (HF). In the absence of IL-17A signaling, Ly6Chi MDMs act as robust phagocytes and are less pro-inflammatory, whereas Ly6Clo monocytes resume their differentiation into MHCII+ macrophages. We propose that MHCII+Ly6Clo MDMs are associated with the reduction of cardiac fibrosis and prevention of the myocarditis sequalae. Copyright 2019 The Author(s). Published by Elsevier Inc. All rights reserved.