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

作者：Xiao, Jiangwei; Huang, Jingwen; Jian, Xiaoting; Wang, Han; Lan, Haiqiang; Liao, Zhaohong; Gu, Ruicai; Hu, Jijie^*; Liao, Hua^*

来源：CELLULAR & MOLECULAR BIOLOGY LETTERS, 2023, 28(1): 15.

DOI：10.1186/s11658-023-00429-w

• Myofiber
• Inflammation
• TGF-beta
• UPR
• IRE1 alpha
• p38 MAPK

Endoplasmic reticulum stress (ERS) and the unfolded protein response (UPR) are involved in various muscle pathological states. The IRE1 alpha arm of UPR can affect immunological properties of myofiber through restraining p38 mitogen-activated protein kinases (MAPK) activation under inflammatory milieu. However, the relevant pathway molecules regulating the initiation of the IRE1 alpha arm in myofiber remain unclear. In this work, expression of transforming growth factor-beta (TGF-beta) and TGF-beta receptor II (TGF-beta r2), and UPR pathway activation were examined in cardiotoxin (CTX)-damaged mouse muscle, which revealed the activation of TGF-beta signaling and UPR in CTX-damaged muscle and in regenerating myofibers. Using control or transgenic mice with TGF-beta r2 deleted in skeletal muscle (SM TGF-beta r2(-/-)) and the derived primary differentiating myogenic precursor cells (MPCs) treated with/without ERS activator or inhibitor, IRE1 alpha pathway inhibitor, or TGF-beta signaling activator, this study further revealed an essential role of intrinsic TGF-beta signaling in regulating muscle cell to express inflammation-related molecules including H-2K(b), H2-E alpha, TLR3, and special myokines. TGF-beta signaling prompted UPR IRE1 alpha arm and restrained p38 MAPK activation in myofiber under inflammatory milieu. This study uncovers a previously unrecognized function of TGF-beta signaling acting as an upstream factor controlling myofiber immune capacities in the inflamed state through the UPR-IRE1 alpha-p38 MAPK pathway.

• 单位
  南方医科大学