Role of selenoprotein P and glutathione peroxidase 3 in macrophage phenotype and skeletal muscle regeneration

Description

Tissue repair after skeletal muscle injury is supported by various cells and notably by macrophages that orchestrate both the inflammatory response, the resolution of inflammation and the recovery phase allowing tissue recovery. After injury, pro-inflammatory macrophages activate myogenic cell proliferation and phagocyte debris. At the time of resolution of inflammation, macrophages switch their phenotype to acquire an anti-inflammatory state, which stimulates the fusion of myogenic cells into multinucleated myofibers. The effectors by which anti-inflammatory macrophages sustain their pro-myogenic effect are poorly known. Thanks to a transcriptomic/secretomic screen comparing the secretome of pro- and anti- inflammatory human macrophages, we identified two anti-oxidant molecules that are two selenoproteins: selenoprotein P (SEPP1) and glutathion peroxidase 3 (GPX3), which functions remain poorly characterized in both muscle biology and inflammation. Macrophage-derived GPX3 and SEPP1 are involved in the function of anti-inflammatory macrophages in the stimulation of the late steps of myogenesis. In vivo, these two selenoproteins are necessary for the homeostasis of skeletal muscle. Moreover, using a skeletal muscle injury model of animals lacking selenoprotein within macrophages (LysMCre/+ Sepp1fl/fl model) we found that the absence of SEPP1 impaired the transition from a pro to an anti-inflammatory phenotype during skeletal muscle regeneration.

Thus, we have demonstrated for the first time the role of selenoproteins secreted by macrophages in tissue repair establishing a link between antioxidant molecules and inflammation resolution.