2. Academic Validation
  3. MDA5 protein mediating persistent ER stress/unfolded protein response contributes to endothelial-mesenchymal-transition of lung microvascular endothelial cell in dermatomyositis

MDA5 protein mediating persistent ER stress/unfolded protein response contributes to endothelial-mesenchymal-transition of lung microvascular endothelial cell in dermatomyositis

  • Cell Commun Signal. 2025 Mar 23;23(1):149. doi: 10.1186/s12964-025-02159-2.
Li-Qin Zhao 1,  Xue-Qing Yang 1,  Qian Niu 1,  Xiao Feng 2,  He-De Zhang 2,  Shu-Yi Ye 1,  Li-Juan Jiang 3,  Fan Yu 1 4,  Hong Ye 5 6 7,  Wan-Li Ma 8 9 10
Affiliations

Affiliations

  • 1 Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
  • 2 Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
  • 3 Department of Rheumatology and Immunology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
  • 4 Key Laboratory of Respiratory Diseases, National Health Commission of China, Wuhan, 430030, China.
  • 5 Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. yehmwl@hust.edu.cn.
  • 6 Key Laboratory of Respiratory Diseases, National Health Commission of China, Wuhan, 430030, China. yehmwl@hust.edu.cn.
  • 7 Basic School of Medicine, Tongji Medical College, Huazhong University of Science and Technology, 13 Hang Kong Road, Wuhan, 430030, China. yehmwl@hust.edu.cn.
  • 8 Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. whmawl@hust.edu.cn.
  • 9 Key Laboratory of Respiratory Diseases, National Health Commission of China, Wuhan, 430030, China. whmawl@hust.edu.cn.
  • 10 Tongji Medical College, Union Hospital, Huazhong University of Science and Technology, 1277 JieFang Avenue, Wuhan, 430022, China. whmawl@hust.edu.cn.
PMID: 40122798 DOI: 10.1186/s12964-025-02159-2
Abstract

Background: Dermatomyositis (DM) is an idiopathic inflammatory myopathy. Anti-MDA5 antibody positive DM (MDA5 + DM) is a distinct subtype of the disease. The model of anti-MDA5 antibody positive DM has been already reported. However, the detailed role and mechanism of MDA5 in vascular damage was still poorly understood.

Methods: Clinical information was retrospectively collected, and a total of 127 DM patients were enrolled. Serum from DM patients and control subjects was used to treat mouse lung microvascular endothelial cells (MVECs) to investigate vascular changes. Western blotting, quantitative real-time polymerase chain reaction (qRT-PCR), immunofluorescence staining, immunoprecipitation, protein mass spectrometry, flow cytometry and bioinformatics analysis were used.

Results: Firstly, clinical data analysis revealed that vascular damage and interstitial lung disease (ILD) was correlated with anti-MDA5 antibody in DM patients. Then, serum from patients was used to treat mouse lung MVECs. Serum from MDA5 + DM patients induced endothelial-mesenchymal-transition (EndMT) in MVECs, and the EndMT in MVECs was mediated by TRB3/ERK/Snai-1 pathway. Next, increased-TRB3 was confirmed induced by persistent ER stress/unfolded protein response (UPR). Notably, persistent ER stress/UPR resulted from MDA5 protein binding with PERK. At last, T cell-derived IFN-β was found to induce MDA5 expression in DM patients.

Conclusion: MDA5 protein mediating persistent ER stress/UPR contributed to EndMT in vascular endothelial cells, which should be involved in MDA5 + DM related ILD.

Keywords

Anti-MDA5 antibody; Dermatomyositis (DM); Endoplasmic reticulum stress (ER stress); Endothelial-Mesenchymal-Transition (EndMT); Interstitial lung disease (ILD); MDA5; Unfolded protein responses (UPR).

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