Club Cells in Nasal Epithelial Repair: Insights From an IL‐13‐Induced Inflammatory Model

ABSTRACT Background Club cells, originating from basal cells, can differentiate into ciliated or goblet cells in the lower respiratory tract, but their role in nasal epithelium during chronic rhinosinusitis with nasal polyps (CRSwNP) is not well understood. We aim to investigate the role of club cells in CRSwNP and their biological mechanism in an IL‐13‐induced inflammation model of human nasal epithelial cells (HNECs). Methods CRSwNP was classified into four endotypes (N − E − , N + E − , N − E + , and N + E + ) based on neutrophil and eosinophil infiltration. The expression of basal (TP63 + ), club (SCGB1A1 + ), ciliated (βIV‐tubulin + ), and goblet cells (MUC5AC + ) was assessed in healthy controls ( n = 23) and CRSwNP ( n = 73) using RT‐qPCR, western blot (WB), and immunofluorescence. The effects of IL‐13, Dupilumab, and STAT6 inhibitor (AS1517499) on cell differentiation were investigated in HNECs ( n = 9) through RT‐qPCR, WB, and flow cytometry (FCM). Results Club and ciliated cells significantly decreased in four endotypes of CRSwNP (all p < 0.001), while basal and goblet cells increased in neutrophilic and eosinophilic CRSwNP, respectively (all p < 0.05). In vitro, IL‐13‐induced significant cilia loss and MUC5AC secretion compared to IFN‐γ and IL‐17A (all p < 0.05), and FCM revealed a shift from SCGB1A1 + βIV‐tubulin + to SCGB1A1 + MUC5AC + cells by IL‐13‐treated (all p < 0.05). Furthermore, Dupilumab mitigated IL‐13‐induced changes more effectively than AS1517499 (all p < 0.05). Conclusions Club cells are crucial in nasal epithelial repair, which is notably compromised in CRSwNP. This impairment is highlighted in an IL‐13‐induced inflammation model of nasal epithelium and further underscored by the therapeutic effect of Dupilumab in restoring epithelial repair mechanisms.