Macrophage scavenger receptor A1 promotes skeletal muscle regeneration after hindlimb ischemia

Abstract

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.

Keywords

scavenger receptor A1 / macrophage / hindlimb ischemia / oncostatin M

Fundings

This work was supported by the National Natural Science Foundation of China (Grant Nos. 82030012, 81670263, 82170444, 82270476, 82270361, and 82100433) and the Natural Science Foundation of the Jiangsu Higher Education Institutions of China (Grant No. 24KJA310003).

Acknowledgments

None.

References

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