Regenerating myofiber directs Tregs and Th17 responses in inflamed muscle through the intrinsic TGF-β signaling-mediated IL-6 production

Abstract

TGF-β is considered to be an important immuno 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 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 up-regulated 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 on 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 on 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.

IRE1α arm of unfolded protein response in muscle-specific TGF-β signaling-mediated regulation of muscle cell immunological properties

“…Our recent work proved that deficiency of TGF-β signaling in muscle cells caused more serious infiltration of macrophages and CD4 T cells at the degeneration stage (D4) and the early stage of regeneration (D7) after myoinjury [ + 26 ]. To further clarify this, the inflammatory response was evaluated using muscle TGF-βr2 deficient mice (SM TGF-βr2 −/− mice), which were hybridized from TGF-βr2-floxed mice and MCK-Cre mice (Additional file 2 : Fig.…”

“…To further clarify this, the inflammatory response was evaluated using muscle TGF-βr2 deficient mice (SM TGF-βr2 −/− mice), which were hybridized from TGF-βr2-floxed mice and MCK-Cre mice (Additional file 2 : Fig. S1) [ 26 ]. As shown in Fig.…”

“…Mice with TGF-βr2 knockout in skeletal muscle (designated as SM TGF-βr2 −/− mice, KO mice) were obtained by crossing TGF-βr2 flox/flox mice with MCK-Cre mice, which were purchased from the Jackson Laboratory. A polymerase chain reaction (PCR) of mouse tail DNA was used to determine the genotypes of generated mice [ 26 ]. TGF-βr2 flox/flox mice were used as the control for KO mice.…”

“…It has been reported that TGF-β signaling can control muscle immune function by directly regulating inflammatory molecules, such as intercellular cell adhesion molecule-1 (ICAM-1) [ 23 ], human leukocyte antigen class I (HLA I) [ 24 ], and interleukin-6 (IL-6) secretion in myofibers [ 25 ]. We recently found TGF signaling elevated in regenerated myofibers and affected the muscle inflammation response [ 26 ]. A question may arise as to whether myofiber-specific TGF-β signaling plays a role in the development of local inflammation after myoinjury, through regulating myofiber ERS and UPR response.…”

Skeletal Muscle Regeneration in Cardiotoxin-Induced Muscle Injury Models

“…Studies have shown that the inflammatory environment induced by interferon gamma (IFN-γ) stimulates the expression of major histocompatibility complex (MHC) and some co-stimulatory molecules from regenerated myofibers or cultured myoblasts and myotubes, which then contribute to the immune response [ 98 ]. Myofibers also mediate the inflammatory response through the activation of transforming growth factor beta (TGF-β)/IL-6 signaling, and direct Th17 and Treg cell responses [ 99 ]. Moreover, oxidative stress during the inflammatory response can also change the structure and function of proteins, which then regulates muscle regeneration in CTX-induced injury [ 100 ].…”