ABSTRACT Backgrounds Nasal epithelial barrier impairment is a crucial pathology in chronic rhinosinusitis with nasal polyps (CRSwNP). However, the mechanisms driving tight junctions (TJs) disruption remain unclear. We aimed to elucidate the role of IL‐13 in TJs breakdown and epithelial remodeling, and to evaluate whether dupilumab can restore epithelial integrity under Type‐2 inflammatory conditions. Methods Differentially expressed TJs‐related genes were identified by integrating the GSE136825 dataset with clinical samples from 23 healthy controls and 73 CRSwNP patients. The effects of IFN‐γ, IL‐13, IL‐17A, and dupilumab on epithelial barrier function and claudin‐10 (CLDN10) expression were investigated in seven human nasal epithelial cells using transepithelial electrical resistance (TER), RT‐qPCR, WB, and immunofluorescence. Statistical analyses were performed using the chi‐square test, one‐way ANOVA, Wilcoxon signed‐rank test, and Spearman's rank correlation. Results CLDN10 was identified as the most significantly downregulated TJs in CRSwNP and negatively correlated with eosinophil infiltration ( r = −0.4414, p < 0.0001). In vitro, IL‐13 markedly reduced CLDN10 and TER levels, and induced epithelial remodeling with fewer club cells and ciliated cells and more goblet cells (all p < 0.05). Additionally, dupilumab effectively mitigated IL‐13‐induced CLDN10 loss, restored barrier integrity, and normalized epithelial alarmins, including IL‐25 and TSLP expression (all p < 0.05). Conclusions IL‐13‐driven Type‐2 inflammation disrupts nasal epithelial barrier integrity by downregulating CLDN10 and altering epithelial cell differentiation. Dupilumab counteracts these effects by restoring CLDN10 expression and epithelial barrier function, highlighting CLDN10 as a crucial mediator of barrier dysfunction and a potential therapeutic target in CRSwNP.
Huang et al. (Wed,) studied this question.