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

Abstract

Objectives: Epithelial-Stromal Interaction 1 (EPSTI1), an interferon-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 dermatomyositis(DM) remains elusive and requires further exploration.

Methods: To investigate EPSTI1 expression in DM, we analyzed 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 (siRNA)-mediated knockdown, we delved into the function and underlying mechanisms of EPSTI1 in DM patients.

Results: EPSTI1 is significantly upregulated in both PBMCs and muscle tissues of DM patients. A notable positive correlation between EPSTI1 expression and interferon-stimulating genes (ISGs) accompanies this upregulation. Furthermore, EPSTI1 levels were markedly elevated in interferon-β(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, interferon signalling, IL-1-mediated signalling, NIK/NF-κB signalling. EPSTI1 was involved in the expression of HLA-A and the secretion of chemokines in myoblasts mediated by IFN-β.

Conclusion: 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 DM patients.