Background: Activation 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. Methods: We 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. Results: Cdh26 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). Conclusion: Taken together, CDH26 is an amplifier of epithelial IL-4R signaling in asthma, and may represent a therapeutic target for airway mucus overproduction.

中文翻译：

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CDH26增强哮喘中气道上皮IL-4受体α信号转导

背景：气道上皮细胞中白介素（IL）-4受体（R）信号的激活导致哮喘中的气道高反应性和粘液过度产生。Cadherin-26（CDH26）是一种与气道上皮细胞极化有关的钙粘蛋白，在哮喘中上调。但是，CDH26在哮喘中的作用仍然未知。我们假设CDH26在哮喘的气道上皮IL-4R信号传导中起作用。方法：在变应原致敏和攻击后，我们测量了Cdh26-/-和WT小鼠的气道阻力，粘液产生，气道炎症和Il-4Rα表达。我们探讨了CDH26在培养的支气管上皮细胞和哮喘患者支气管刷中IL-4R信号传导，粘蛋白基因和嗜酸性趋化因子表达中的作用。结果：Cdh26缺乏症几乎阻塞了气道粘液的过度产生，并在变应性气道疾病的鼠模型中抑制了AHR和气道嗜酸性粒细胞增多。有趣的是，在Cdh26-/-小鼠中，气道上皮中的Il-4Rα表达显着降低。在培养的人支气管上皮细胞中，CDH26抑制可抑制IL-13（IL-4R的配体）诱导IL-4Rα和IL-13Rα1表达，并抑制下游Jak1和Stat6磷酸化。此外，CDH26组合可抑制IL-13诱导的MUC5AC，MUC5B和嗜酸性趋化因子CCL11，CCL24，CCL26的表达。相反，CDH26过表达增强了IL-13诱导的IL-4Rα信号传导的激活。在哮喘患者中，CDH26是支气管刷中11种钙黏着蛋白中唯一被上调的一种。CDH26表达与上皮IL-4Rα，MUC5AC表达，痰嗜酸性粒细胞增多和呼出气一氧化氮（FeNO）显着相关。结论：