1. Academic Validation
  2. IRE1α arm of unfolded protein response in muscle-specific TGF-β signaling-mediated regulation of muscle cell immunological properties

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

  • Cell Mol Biol Lett. 2023 Feb 27;28(1):15. doi: 10.1186/s11658-023-00429-w.
Jiangwei Xiao # 1 Jingwen Huang # 1 Xiaoting Jian 1 Han Wang 1 Haiqiang Lan 1 Zhaohong Liao 1 Ruicai Gu 2 Jijie Hu 3 Hua Liao 4
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Department of Anatomy, School of Basic Medical Science, Southern Medical University, Guangzhou, 510515, China.
  • 2 Department of Cell Biology, University of Oklahoma Health Science Center, Oklahoma City, OK, USA.
  • 3 Department of Orthopaedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. hjj0610@163.com.
  • 4 Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Department of Anatomy, School of Basic Medical Science, Southern Medical University, Guangzhou, 510515, China. hua-liao@163.com.
  • # Contributed equally.
Abstract

Endoplasmic reticulum stress (ERS) and the unfolded protein response (UPR) are involved in various muscle pathological states. The IRE1α 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 IRE1α arm in myofiber remain unclear. In this work, expression of transforming growth factor-beta (TGF-β) and TGF-β Receptor II (TGF-βr2), and UPR pathway activation were examined in cardiotoxin (CTX)-damaged mouse muscle, which revealed the activation of TGF-β signaling and UPR in CTX-damaged muscle and in regenerating myofibers. Using control or transgenic mice with TGF-βr2 deleted in skeletal muscle (SM TGF-βr2-/-) and the derived primary differentiating myogenic precursor cells (MPCs) treated with/without ERS activator or inhibitor, IRE1α pathway inhibitor, or TGF-β signaling activator, this study further revealed an essential role of intrinsic TGF-β signaling in regulating muscle cell to express inflammation-related molecules including H-2Kb, H2-Eα, TLR3, and special myokines. TGF-β signaling prompted UPR IRE1α arm and restrained p38 MAPK activation in myofiber under inflammatory milieu. This study uncovers a previously unrecognized function of TGF-β signaling acting as an upstream factor controlling myofiber immune capacities in the inflamed state through the UPR-IRE1α-p38 MAPK pathway.

Keywords

IRE1α; Inflammation; Myofiber; TGF-β; UPR; p38 MAPK.

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