Cadherin-26 Amplifies Airway Epithelial IL-4 Receptor Signaling in Asthma

Activation of IL-4R (IL-4 receptor) signaling in airway epithelial cells leads to airway hyperresponsiveness and mucus overproduction in asthma. CDH26 (cadherin-26), a cadherin implicated in the polarization of airway epithelial cells, is upregulated in asthma. However, the role of CDH26 in asthma remains unknown. In this study, we demonstrated that Cdh26 deficiency significantly reduced airway mucus overproduction, airway hyperresponsiveness, and airway eosinophilia in a murine model of allergic airway disease. Interestingly, allergen-induced Il-4Ra upregulation 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-4R alpha and IL-13R alpha 1 (IL-13 receptor alpha 1) upregulation; and suppressed downstream Jak1 (Janus kinase 1) and Stat6 (signal transducer and activator of transcription 6) phosphorylation. Moreover, CDH26 knockdown inhibited IL-13-induced MUC5AC and eosinophilic chemokine expression. These results suggest that CDH26 plays a key role in epithelial IL-4R signaling activation and downstream effectors. In contrast, CDH26 overexpression amplified IL-13-activated IL-4R signaling in BEAS-2B cells. In the airway epithelium of patients with asthma, IL-4R alpha expression was elevated, and CDH26 was the only cadherin that was upregulated among 11 cadherin family members. CDH26 expression was strongly correlated with epithelial IL-4R alpha and MUC5AC expression, sputum eosinophilia, and fractional exhaled nitric oxide in patients with asthma. Taken together, we identified CDH26 as a key regulator of epithelial IL-4R signaling in asthma and a potential therapeutic target for IL-4R-mediated allergic diseases.

Automated summary

CDH26 serves as a key regulator of epithelial IL-4R signaling in asthma, playing a role in airway hyperresponsiveness, mucus overproduction, and eosinophilia. It modulates IL-4R signaling by regulating IL-13 binding, IL-4R alpha expression, and downstream phosphorylation of Jak1 and Stat6. CDH26 may serve as a potential therapeutic target for IL-4R-mediated allergic diseases.