FAP-derived CCL2 is required for adequate monocyte/macrophage infiltration to support acute skeletal muscle injury...

Repair of acutely injured skeletal muscle relies on an adequate inflammatory response predominated by monocyte/macrophage infiltration. The process requires injured muscles to produce C-C chemokine ligand 2 (CCL2). The present study identified fibro/adipogenic progenitors (FAPs) as the primary source of CCL2 in acutely injured muscle, where the pro-inflammatory subcluster of FAPs expanded rapidly and expressed the highest level of CCL2. FAP-specific deletion of Ccl2 largely abolished CCL2 production by acutely injured muscle, reducing monocyte/macrophage infiltration and impairing muscle regeneration. In vitro, the CCL2 expression by both mouse and human FAPs was induced by danger signal-containing muscle homogenates through Toll-like receptor signaling. The CCL2 expression by mouse FAPs was also induced by infiltrating neutrophils, partly through their secretion of pro-inflammatory cytokines. Our findings suggest an important immune sentinel role for FAPs, as they sense muscle damage, produce CCL2 to recruit inflammatory monocytes, and promote injury repair.