Regenerating myofiber with activating of TGF-β signaling contributes to macrophage efferocytosis through enhancing Tregs response in inflamed muscle

Background: This study aimed to investigate the role of myofiber-specific TGF-β signaling in the development of muscle inflammation by modulating Treg-cell-mediated macrophage efferocytosis. Methods: mice. Apoptotic cells were generated by UV irradiation prior to transfer into inflamed muscle. Results: Deficiency in muscle TGF-β signaling resulted in more severe muscle inflammation, characterized by an increased number of M1 macrophages and a decreased number of M2 macrophages. Notably, the absence of muscle TGF-β signaling impaired the efferocytic capacity of macrophages and reduced the proportion of Tregs in inflamed muscle. Further, we monitored that activation of intrinsic TGF-β signaling suppresses myofiber IL-6 production, which in turn impacted on IL-13 production from Tregs accumulated in damaged muscle. This ultimately facilitates IL-10-STAT3-Vav1-mediated macrophage efferocytosis in inflamed muscle. Conclusions: Our findings establish a link between muscle-specific TGF-β signaling, myokine IL-6, Tregs derived IL-13 and macrophage efferocytosis in inflamed muscle. These results suggest that therapeutic targeting of this axis may hold promise for promoting muscle regeneration.