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

• Published in: Cell communication and signaling Vol. 23; no. 1; pp. 149 - 17
• Main Authors: Zhao, Li-Qin, Yang, Xue-Qing, Niu, Qian, Feng, Xiao, Zhang, He-De, Ye, Shu-Yi, Jiang, Li-Juan, Yu, Fan, Ye, Hong, Ma, Wan-Li
• Format: Journal Article
• Language: English
• Published: London BioMed Central 23.03.2025; BioMed Central Ltd; BMC
• Subjects: Adult; Animals; Anti-MDA5 antibody; Antibodies; Apoptosis; B cells; Bioinformatics; Biomedical and Life Sciences; Biopsy; Blood circulation disorders; Cell Biology; Cell differentiation; Complications and side effects; Cytokines and Growth Factors; Dermatomyositis; Dermatomyositis (DM); Dermatomyositis - metabolism; Dermatomyositis - pathology; Development and progression; Disease; Endoplasmic reticulum; Endoplasmic Reticulum Stress; Endoplasmic reticulum stress (ER stress); Endothelial cells; Endothelial Cells - metabolism; Endothelial Cells - pathology; Endothelial-Mesenchymal-Transition (EndMT); Endothelium; Enzymes; Epithelial cells; Epithelial-Mesenchymal Transition; Female; Flow cytometry; Health aspects; Homeostasis; Humans; Immunofluorescence; Immunoprecipitation; Interferon-Induced Helicase, IFIH1 - metabolism; Interstitial lung disease (ILD); Kinases; Life Sciences; Lung - blood supply; Lung - pathology; Lung diseases; Lung diseases, Interstitial; Lymphocytes T; Male; Mass spectrometry; Mass spectroscopy; MDA5; Medical research; Mice; Microvasculature; Microvessels - pathology; Middle Aged; Myopathy; Patients; Pattern recognition receptors; Phosphorylation; Polymerase chain reaction; Protein binding; Protein folding; Protein-Ligand Interactions; Proteins; Receptors; Risk factors; Skin; Stem cells; T cells; Transcription factors; Vascular endothelium; Viral antibodies; Western blotting; β-Interferon; China; Interstitial lung disease (ILD); Anti-MDA5 antibody; Unfolded protein responses (UPR); Endoplasmic reticulum stress (ER stress); Dermatomyositis (DM); Endothelial-Mesenchymal-Transition (EndMT); MDA5
• ISSN: 1478-811X; 1478-811X
• DOI: 10.1186/s12964-025-02159-2

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.