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

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.