Macrophage scavenger receptor A1 promotes skeletal muscle regeneration after hindlimb ischemia

The macrophage-mediated inflammatory response is crucial for the recovery of skeletal muscle following ischemia. Therefore, macrophage-based therapeutic targets need to be explored for ischemic disease. In the current study, we found that the mRNA levels of scavenger receptor A1 (Sr-a1) were elevated in patients with critical limb ischemia, based on an analysis of the Gene Expression Omnibus data. We then investigated the role and underlying mechanisms of macrophage SR-A1 in a mouse hindlimb ischemia (HLI) model. Compared with the Sr-a1^fl/fl mice, the Lyz^Cre/+/Sr-a1^flox/flox (Sr-a1^ΔMΦ) mice showed significantly reduced laser Doppler blood flow in the ischemic limb on day seven after HLI. Consistently, histological analysis revealed that the ischemic limb of the Sr-a1^ΔMΦ mice exhibited more severe and prolonged necrotic morphology, inflammation, fibrosis, decreased vessel density, and delayed regeneration than that of the control Sr-a1^fl/fl mice. Furthermore, restoring wild-type myeloid cells to the Sr-a1 knockout mice effectively improved the Doppler perfusion in the ischemic limb and mitigated skeletal muscle damage seven days after HLI. Consistent with these in vivo findings, co-cultivating macrophages with the mouse myoblast cell line C2C12 revealed that the Sr-a1^−/− bone marrow macrophages significantly inhibited myoblast differentiation in vitro. Mechanistically, SR-A1 enhanced the skeletal muscle regeneration in response to HLI by inhibiting oncostatin M production via suppression of the NF-κB signaling activation. These findings indicate that SR-A1 may be a promising candidate protein to improve tissue repair and regeneration in peripheral ischemic arterial disease.