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This research investigates how myofiber-specific TGF-β signaling influences macrophage efferocytosis and muscle inflammation.

April 26, 2026Open Access

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

Key Points

This research investigates how myofiber-specific TGF-β signaling influences macrophage efferocytosis and muscle inflammation.
Injury induced by CTX in tibialis anterior muscle of control and transgenic mice with specific TGF-β receptor deletion.
Assessment of Treg activation markers and inflammatory mediators via qRT-PCR and various analysis techniques.
In vitro co-culture system involving Tregs, macrophages, and myogenic precursor cells to study efferocytosis processes.
TGF-β signaling deficiency led to exacerbated muscle inflammation with increased M1 and decreased M2 macrophages.
Impaired macrophage efferocytosis and reduced Treg proportions were observed in inflamed muscle without TGF-β signaling.
Enhanced TGF-β signaling decreased myofiber IL-6, positively influencing Tregs' IL-13 production and macrophage efferocytosis.

Abstract

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 CTX-induced muscle injury was performed in the tibialis anterior (TA) of control (TGF-βr2 flox/flox ) and transgenic mice with skeletal muscle-specific deletion of TGF-β receptor 2 (SM TGF-βr2 −/− ). Gene levels of regulatory T cell (Treg) activation markers and inflammatory mediators produced by macrophages or Tregs were assessed using qRT-PCR. Intramuscular infiltration of Tregs and macrophages, as well macrophage phenotypes, efferocytic function, and associated signaling molecules, were evaluated using hematoxylin and eosin (HE) staining, immunofluorescence, immunoblotting and FACS analysis. The correlation of myofibers with Tregs-mediated macrophage efferocytosis were addressed under an in vitro co-culture system, which including Tregs, macrophages, and the differentiated myogenic precursor cells (MPC-myotubes) isolated from control or SM TGF-βr2 −/− 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.

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