High levels of EPSTI1 enhance IFN-β-mediated HLA-A expression and chemokine secretion in myoblasts in dermatomyositis.

Abstract

Epithelial-Stromal Interaction 1 (EPSTI1), an IFN-related gene that has emerged as a gene of notable interest, plays a multifaceted role in cellular function and disease processes. However, the precise role of EPSTI1 in the context of DM remains elusive and requires further exploration. To investigate EPSTI1 expression in DM, we analysed two transcriptome datasets, peripheral blood mononuclear cells (PBMCs) and muscle tissues from our DM cohort. We further validated the findings using RT-qPCR and immunohistochemical staining within our idiopathic inflammatory myopathy (IIM) cohort. Through small interfering RNA-mediated knockdown, we delved into the function and underlying mechanisms of EPSTI1 in DM patients. EPSTI1 is significantly upregulated in both PBMCs and muscle tissues of DM patients. A notable positive correlation between EPSTI1 expression and IFN-stimulating genes accompanies this upregulation. Furthermore, EPSTI1 levels were markedly elevated in IFN-β-stimulated myoblasts. Functional studies have shown that downregulation of EPSTI1 inhibits multiple immune and inflammatory pathways, including antigen processing and presentation, chemokine-mediated signalling, IFN signalling, IL-1-mediated signalling, nuclear factor (NF)-κB-inducing kinase (NIK)/NF-κB signalling. EPSTI1 was involved in the expression of HLA-A and the secretion of chemokines in myoblasts mediated by IFN-β. EPSTI1 might play an essential role in promoting muscle inflammation in DM by regulating the expression of HLA-A and the secretion of chemokines in myoblasts. Targeting EPSTI1 may represent a novel therapeutic approach for reducing muscle inflammation and damage in dermatomyositis (DM) patients.