Airway epithelial dual oxidase 1 mediates allergen-induced IL-33 secretion and activation of type 2 immune responses.
Airway epithelial dual oxidase 1 mediates allergen-induced IL-33 secretion and activation of type 2 immune responses.
复制标题
DOI：
10.1016/j.jaci.2015.10.003
复制
发表时间：
2016-05
期刊：
影响因子：
--
通讯作者：
van der Vliet A
中科院分区：
文献类型：
--
作者：
Hristova M;Habibovic A;Veith C;Janssen-Heininger YM;Dixon AE;Geiszt M;van der Vliet A
白细胞介素 (IL)-1 家族成员 IL-33 在针对过敏原的 2 型先天免疫反应中发挥着关键作用，并且是过敏性哮喘的重要介质。过敏原激发上皮 IL-33 分泌的机制仍知之甚少。基于先前的研究结果表明 NADPH 氧化酶 DUOX1 参与上皮伤口反应，我们探讨了 DUOX1 在过敏原诱导的 IL-33 分泌中的潜在参与以及哮喘受试者气道的潜在改变。培养的人或鼠气道上皮细胞或小鼠受到链格孢或屋尘螨 (HDM) 的急性攻击，并测定 IL-33 的分泌和随后 2 型反应的激活。使用 siRNA 方法和 DUOX1 缺陷小鼠探讨了 DUOX1 的作用。评估来自健康或哮喘受试者的培养鼻上皮细胞的 DUOX1 表达和过敏原诱导的反应。体外或体内过敏原攻击导致气道上皮 IL-33 快速分泌，这主要取决于 DUOX1 介导的上皮表皮生长因子受体 (EGFR) 和蛋白酶 calpain-2 的激活，通过氧化还原依赖性机制，涉及 EGFR 和酪氨酸激酶 Src 内的半胱氨酸氧化。研究发现，与非哮喘受试者的鼻上皮细胞相比，过敏性哮喘受试者的原代鼻上皮细胞表达升高的 DUOX1 和 IL-33，并且在响应过敏原攻击时显示出 IL-33 分泌增强。我们的研究结果表明，上皮 DUOX1 是对常见空气过敏原的先天气道 2 型免疫反应的 IL-33 依赖性激活的关键介质，并表明增强的 DUOX1 表达和 IL-33 分泌可能是过敏性哮喘的重要特征。
The interleukin (IL)-1 family member IL-33 plays a critical role in type-2 innate immune responses to allergens, and is an important mediator of allergic asthma. The mechanisms by which allergens provoke epithelial IL-33 secretion are still poorly understood. Based on previous findings indicating involvement of the NADPH oxidase DUOX1 in epithelial wound responses, we explored the potential involvement of DUOX1 in allergen-induced IL-33 secretion and potential alterations in airways of subjects with asthma. Cultured human or murine airway epithelial cells or mice were subjected to acute challenge with Alternaria alternata or house dust mite (HDM), and secretion of IL-33 and activation of subsequent type 2 responses were determined. The role of DUOX1 was explored using siRNA approaches and DUOX1-deficient mice. Cultured nasal epithelial cells from healthy or asthmatic subjects were evaluated for DUOX1 expression and allergen-induced responses. In vitro or in vivo allergen challenge resulted in rapid airway epithelial IL-33 secretion, which critically depended on DUOX1-mediated activation of epithelial epidermal growth factor receptor (EGFR) and the protease calpain-2, via a redox-dependent mechanism involving cysteine oxidation within EGFR and the tyrosine kinase Src. Primary nasal epithelial cells from subjects with allergic asthma were found to express elevated DUOX1 and IL-33, and demonstrated enhanced IL-33 secretion in response to allergen challenge compared to nasal epithelial cells from non-asthmatic subjects. Our findings implicate epithelial DUOX1 as a pivotal mediator of IL-33-dependent activation of innate airway type 2 immune responses to common airborne allergens, and indicate that enhanced DUOX1 expression and IL-33 secretion may present important contributing features of allergic asthma.