Background <p>Eosinophilic asthma, affecting more than 50% of adult asthma patients, demonstrates airway inflammation severity directly correlated with eosinophil infiltration levels. While transepithelial eosinophil migration constitutes a pivotal step in airway inflammation pathogenesis, the regulatory mechanisms remain undefined. We aim to investigate how desmoglein-2 (DSG2), which is a key desmosomal cadherin mediating epithelial intercellular adhesion, regulates eosinophil transmigration across the bronchial epithelial barrier.</p> Methods <p>DSG2 protein levels were measured by ELISA in asthma patients’ and healthy volunteers’ serum. In vitro, a lower level of DSG2 in bronchial cells weakened barrier integrity, boosting eosinophil migration. To further investigate the role of DSG2 in eosinophilic asthma, in vivo mouse studies were conducted. These studies employed an adeno-associated virus to modulate DSG2 expression (either downregulation or upregulation) or utilized exogenous supplementation with recombinant DSG2 protein, followed by assessment of their effects on ovalbumin (OVA)/house dust mite (HDM)-induced eosinophilic asthma.</p> Results <p>DSG2 was primarily expressed in human bronchial epithelial cells and was decreased in asthma patients compared to healthy individuals. The serum levels of DSG2 protein were significantly lower in asthmatic patients compared to healthy subjects. A negative correlation was observed between serum DSG2 protein levels and the count of peripheral blood eosinophils in asthma patients. Furthermore, Th2 cytokines interleukin-4 (IL-4) and interleukin-13 (IL-13) downregulated the expression of DSG2 protein. In bronchial epithelial cells, DSG2 protein played a crucial role in maintaining epithelial barrier function and cell adhesion. A reduction in its expression led to enhanced transepithelial migration of eosinophils in vitro. Consistent with these findings, a murine model of eosinophilic asthma exhibited decreased DSG2 expression and increased eosinophil infiltration in the airways. Notably, this eosinophil infiltration was exacerbated by the downregulation of DSG2. Critically, in both in vivo and in vitro experiments, overexpression of DSG2 in bronchial epithelial cells or exogenous addition of recombinant DSG2 protein partially reversed asthma-associated epithelial barrier impairment and alleviated eosinophilic airway inflammation.</p> Conclusion <p>We elucidated the crucial role of DSG2 in bronchial epithelial cells during eosinophilic asthma development, focusing on its maintenance of desmosome structure and facilitation of eosinophil migration across the airway epithelium.</p> Graphical Abstract <p></p>