Regenerating myofiber directs Tregs and Th17 responses in inflamed muscle through the intrinsic TGF-β signaling-mediated IL-6 production.
American journal of physiology. Endocrinology and metabolism(2022)
Abstract
Transforming growth factor-β (TGF-β) is considered to be an important immune regulatory cytokine. However, it remains unknown whether and how the muscle fiber specific-TGF-β signaling is directly involved in intramuscular inflammatory regulation by affecting T cells. Here, we addressed these in a mouse tibialis anterior muscle Cardiotoxin injection-induced injury repair model in muscle creatine kinase (MCK)-Cre control or transgenic mice with TGF-β receptor II (TGF-βr2) being specifically deleted in muscle cells (SM TGF-βr2-/-). In control mice, TGF-β2 and TGF-βr2 were found significantly upregulated in muscle after the acute injury. In mutant mice, deficiency of TGF-β signaling in muscle cells caused more serious muscle inflammation, with the increased infiltration of macrophages and CD4+ T cells at the degeneration stage (D4) and the early stage of regeneration (D7) after myoinjury. Notably, the loss of TGF-β signaling in myofibers dramatically affected CD4+ T cell function and delayed T cells withdrawal at the later stage of muscle regeneration (D10 and D15), marked by the elevated Th17, but the impaired Tregs response. Furthermore, in vivo and in vitro, the intrinsic TGF-β signaling affected immune behaviors of muscle cells and directed CD4+ T cells differentiation by impairing IL-6 production and release. It suggests that local muscle inflammation can be inhibited potentially by directly activating the TGF-β signaling pathway in muscle cells to suppress Th17, but induce Tregs responses. Thus, according to the results of this study, we found a new idea for the control of local acute inflammation in skeletal muscle.NEW & NOTEWORTHY Myofiber mediates muscle inflammatory response through activating the intrinsic TGF-β signaling. The specific TGF-β signaling activation contributes to myofiber IL-6 production and directs muscle-specific Th17 and Treg cell responses.
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