MicroRNAs in autoimmune connective tissue diseases: Pathogenic roles, clinical implications, and therapeutic potential

Abstract

MicroRNAs (miRNAs) are key post-transcriptional regulators of gene expression involved in immune homeostasis, inflammation, fibrosis, and vascular remodeling. Their dysregulation has been increasingly implicated in the pathogenesis of autoimmune connective tissue diseases (ACTDs). Recent studies have identified numerous differentially expressed miRNAs associated with immune dysregulation and progressive tissue injury in these disorders. This review summarizes current evidence on the pathogenic roles of miRNAs in ACTDs, including systemic sclerosis (SSc), mixed connective tissue disease (MCTD), dermatomyositis (DM), Sjögren's syndrome (SS), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE). In SSc, miR-145 promotes myofibroblast differentiation and contributes to fibrosis, whereas miR-21a-5p overexpression is associated with increased numbers of cells producing proinflammatory cytokines, including TNF-α, IL-1β, IL-6, and IL-17. In MCTD, preliminary studies have identified associations between miRNA-related alterations and immune or inflammatory pathways, including genetic variation involving miR-146a and exploratory changes in miR-155 expression. However, current evidence remains limited and associative and does not establish definitive roles for these miRNAs in MCTD pathogenesis. In DM, miR-125a-3p, miR-1246, and miR-3614–5p have been associated with dysregulated autophagy and inflammatory responses. In SS, miR-181d-5p is downregulated and is negatively correlated with glandular TNF-α mRNA expression, whereas miR-150–5p plays an important role in B-cell maturation and activation. In RA, miR-124a is associated with synovial hyperplasia and increased production of inflammatory mediators, such as MCP-1, whereas reduced miR-34a expression affects Th17/Treg differentiation and is associated with structural joint damage. In SLE, dysregulation of miR-142–3p and miR-122–5p is associated with disease activity and alterations in T-cell regulation and B-cell activation. Collectively, current evidence indicates that miRNA dysregulation contributes to key immunological, inflammatory, and fibrotic processes underlying ACTDs. These findings also highlight the potential of miRNAs as biomarkers for disease monitoring and as molecular targets for the development of novel therapeutic strategies.