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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-4R\u03b1 upregulation in airway epithelium was markedly reduced in Cdh26 \u00a0\u2212\/\u2212 mice. In cultured human bronchial epithelial cells, CDH26 knockdown inhibited IL-13, a ligand for IL-4R; induced IL-4R\u03b1 and IL-13R\u03b11 (IL-13 receptor \u03b11) upregulation; and suppressed downstream Jak1 (Janus kinase 1) and Stat6 (signal transducer and activator of transcription 6) phosphorylation. Moreover, CDH26 knockdown inhibited IL-13\u2013induced 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\u2013activated IL-4R signaling in BEAS-2B cells. In the airway epithelium of patients with asthma, IL-4R\u03b1 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\u03b1 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\u2013mediated allergic diseases.<\/jats:p>","DOI":"10.1165\/rcmb.2021-0109oc","type":"journal-article","created":{"date-parts":[[2022,8,5]],"date-time":"2022-08-05T12:31:22Z","timestamp":1659702682000},"page":"539-549","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":20,"title":["Cadherin-26 Amplifies Airway Epithelial IL-4 Receptor Signaling in Asthma"],"prefix":"10.1093","volume":"67","author":[{"given":"Yuchen","family":"Feng","sequence":"first","affiliation":[{"name":"Division of Respiratory and Critical Care Medicine, Department of Internal Medicine, and"},{"name":"Key Laboratory of Respiratory Diseases, National Health Commission of People\u2019s Republic of China, Wuhan, 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