DNA Methylation and microRNA regulation of the IL-33/TSLP–Th2

Abstract

Bronchial asthma is a heterogeneous chronic inflammatory disease of the airways that results from a complex interaction between genetic predisposition and environmental factors. Among these, respiratory viral infections—including rhinovirus, respiratory syncytial virus, influenza virus, and SARS-CoV-2—are recognized not only as the leading cause of asthma exacerbations but also as major contributors to persistent airway inflammation. A central role in virus-induced immune responses is played by the epithelial alarmin axis comprising interleukin-33 (IL-33) and thymic stromal lymphopoietin (TSLP), whose activation drives Th2-mediated inflammation, resulting in eosinophilic infiltration, airway hyperresponsiveness, and bronchial remodeling. The aim of the present review is to examine the relationship between the epithelial alarmins IL-33 and TSLP and epigenetic modifications, particularly DNA methylation and microRNA expression, in asthma pathogenesis, with special emphasis on respiratory viral infections as triggers of these molecular events. Current evidence on the mechanisms by which respiratory viruses modulate IL-33- and TSLP-dependent signaling through epigenetic regulations are summarized. Particular attention is given to DNA methylation and microRNA-mediated regulation of genes encoding epithelial alarmins and their downstream signaling pathways. Aberrant epigenetic regulation contributes to persistent Th2-driven inflammation, enhanced production of pro-inflammatory cytokines, and increased susceptibility to recurrent viral infections and non-infectious triggers. In addition, microRNAs can regulate the expression of epithelial alarmins and serve as potential biomarkers of asthma activity and response to treatment. Studying their role in the interaction between viruses and epigenetic mechanisms broadens our understanding of the pathogenesis of asthma and opens up new possibilities for precision therapy.