Individual subsets of alternatively-activated macrophages differentially contribute to tissue repair and the resolution of inflammation

Abstract Although alternatively-activated macrophages (AAM) have been implicated in the resolution of inflammation and tissue repair, their exact role, heterogeneity and origin in vivo remain incompletely defined. Here we show that distinct subsets of macrophages can acquire alternatively activated phenotypes in response to tissue injury where these cellular subsets display contrasting spatiotemporal dynamics and differentially contribute to the resolution of inflammation and tissue repair. By studying a model of cardiotoxin-induced muscle injury, we identify a population of monocyte-derived AAM characterized by expression of arginase-1 (Arg-1) and triggering receptor expressed on myeloid cells 2 (Trem2) that emerged in response to injury and fostered clearance of dying neutrophils and necrotic myofibers as well as the subsequent resolution of inflammation. A second population of AAM, which were marked by robust expression of resistin-like molecule alpha (Relmα) and mannose receptor C-type 1 (CD206), displayed a predominantly resident character and clustered around capillaries where they coordinated the recruitment of eosinophils as well as the subsequent process of tissue repair. Our data thus indicate a substantial heterogeneity among AAM subsets and help to define their specialized functions and roles during inflammation and tissue repair.