Cadherin 26 Amplifies Airway Epithelial IL-4 Receptor α Signaling In Asthma

Background: Activation of interleukin(IL)-4 receptor(R)signaling in airway epithelial cells leads to airway hyperresponsiveness(AHR)and mucus overproduction in asthma.Cadherin-26(CDH26),a cadherin implicated in the polarization of airway epithelial cells,is upregulated in asthma.However,the role of CDH26 in asthma remains unknown.Objective:To explore the role of CDH26 in the pathogenesis of bronchial asthma.Methods: We examined airway resistance,mucus production,airway inflammation,and Il-4Rα expression in Cdh26-/-and WT mice after allergen sensitization and challenge.We explored the role of CDH26 in IL-4R signaling,mucin genes expression and eosinophilic chemokine genes expression in cultured bronchial epithelial cells and bronchial brushings from asthma patients.Results: Cdh26 deficiency led to less airway mucus production,reduced AHR,and decreased airway eosinophilic infiltration in a murine model of allergic airway inflammation disease.Interestingly,airway epithelial Il-4Rα expression was markedly reduced in Cdh26-/-mice.In cultured human bronchial epithelial cells,CDH26 knockdown inhibited IL-13,a ligand for IL-4R,-induced IL-4Rα and IL-13Rα1 expression,and suppressed the downstream Jak1 and Stat6 phosphorylation.Moreover,CDH26 knockdown inhibited IL-13-induced MUC5 AC,MUC5B and eosinophilic chemokines CCL11,CCL24,CCL26 expression.In contrast,CDH26 overexpression intensified IL-13-induced activation of IL-4Rα signaling.In bronchial brushings of asthma patients,CDH26 was the only one upregulated member of the 11 cadherins.CDH26 expression significantly correlated with epithelial IL-4Rα and MUC5 AC expression,sputum eosinophilia,and fractional exhaled nitric oxide(Fe NO).Conclusion: CDH26 is an amplifier of epithelial IL-4R signaling in asthma,and may represent a potential therapeutic target for airway mucus overproduction and eosinophilc inflammation.