CDH26 amplifies airway epithelial IL-4 receptor α signaling in asthma

ABSTRACTBackgroundActivation of interleukin (IL)-4 receptor (R) signaling in airway epithelial cells leads to airway hyperresponsiveness and mucus overproduction in asthma. Cadherin-26 (CDH26), a cadherin implicated in polarization of airway epithelial cells, is upregulated in asthma. However, the role of CDH26 in asthma remains unknown. We hypothesize that CDH26 plays a role in airway epithelial IL-4R signaling in asthma.MethodsWe measured 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 and eosinophilic chemokine expression in cultured bronchial epithelial cells and bronchial brushings from asthma patients.ResultsCdh26 deficiency nearly blocked airway mucus overproduction, and suppressed AHR and airway eosinophilia in a murine model of allergic airway disease. Interestingly, Il-4Rα expression in airway epithelium 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 MUC5AC, MUC5B and eosinophilic chemokines CCL11, CCL24, CCL26 expression. In contrast, CDH26 overexpression intensified IL-13-induced activation of IL-4Rα signaling. In asthma patients, CDH26 was the only one upregulated of 11 cadherins in bronchial brushings. CDH26 expression significantly correlated with epithelial IL-4Rα, MUC5AC expression, sputum eosinophilia and fractional exhaled nitric oxide (FeNO).ConclusionTaken together, CDH26 is an amplifier of epithelial IL-4R signaling in asthma, and may represent a therapeutic target for airway mucus overproduction.