Cadherin‐26 Facilitates Transepithelial Migration of Eosinophils in Eosinophilic Chronic Rhinosinusitis

ABSTRACT Background Eosinophilic chronic rhinosinusitis with nasal polyps (eCRSwNP) is characterized by persistent sinonasal inflammation and marked eosinophilic infiltration. Although the relationship between eosinophils and NP formation has been extensively studied, the mechanisms governing eosinophil transepithelial migration into the nasal mucosa remain poorly understood. Cadherin‐26 (CDH26), an epithelial adhesion molecule that binds to integrins α4 (ITGA4) and αE, has been implicated in eosinophilic inflammation and may play a critical role in eosinophil recruitment and tissue infiltration. Objective This study aimed to investigate the role and underlying mechanism of CDH26 in facilitating eosinophil transepithelial migration in patients with eCRSwNP. Methods Single‐cell ribonucleic acid (RNA) sequencing and immunohistochemistry (IHC) were performed on nasal tissues from patients with eCRSwNP, non‐eCRSwNP, chronic rhinosinusitis without nasal polyps (CRSsNP), and healthy controls to evaluate CDH26 expression. Human primary nasal epithelial cells (hPNECs) were stimulated in vitro with interleukin‐4 (IL‐4) or IL‐13, and CDH26 expression was assessed via reverse transcription polymerase chain reaction (RT‐PCR), western blotting, and IHC. The effect of IL‐4 receptor blockade using Dupilumab was evaluated in monolayer cultures. ITGA4 expression in EoL‐1 eosinophil‐like cells was measured by flow cytometry, and their interaction with recombinant CDH26 was evaluated using cell adhesion and Transwell migration assays. Results CDH26 expression was significantly upregulated in eCRSwNP tissues compared to that in other groups. IL‐4 and IL‐13 stimulation induced CDH26 expression in hPNECs, which was dose‐dependently inhibited by Dupilumab. EoL‐1 cells expressed ITGA4 and adhered to recombinant CDH26 in vitro. Th2 cytokine stimulation enhanced EoL‐1 cell transepithelial migration, which was significantly reduced by CDH26 knockdown or Dupilumab treatment. Conclusion Th2 cytokine‐induced upregulation of epithelial CDH26 facilitates eosinophil transepithelial migration, potentially via ITGA4 interaction. Thus, CDH26 may represent a novel therapeutic target for managing eCRSwNP.