Key Points IL-33 autoamplifies the IL-33/ST2 pathway by inducing its own and ST2 expression. Airway epithelial cells are the major source of endogenous IL-33 production. An intact endogenous IL-33/ST2 pathway is necessary for asthma-like mouse models. IL-33 and its receptor ST2 are contributing factors to airway inflammation and asthma exacerbation. The IL-33/ST2 signaling pathway is involved in both the onset and the acute exacerbations of asthma. In this study, we address the role of endogenous IL-33 and its autoamplification of the IL-33/ST2 pathway in Ag-dependent and Ag-independent asthma-like models. Wild-type, IL-33 knockout, ST2 knockout mice were either intratracheally administrated with 500 ng of rIL-33 per day for four consecutive days or were sensitized and challenged with OVA over 21 d. In wild-type mice, IL-33 or OVA induced similar airway hyperresponsiveness and eosinophilic airway inflammation. IL-33 induced its own mRNA and ST2L mRNA expression in the lung. IL-33 autoamplified itself and ST2 protein expression in airway epithelial cells. OVA also induced IL-33 and ST2 protein expression. In IL-33 knockout mice, the IL-33– and OVA-induced airway hyperresponsiveness and eosinophilic airway inflammation were both significantly attenuated, whereas IL-33–induced ST2L mRNA expression was preserved, although no autoamplification of IL-33/ST2 pathway was observed. In ST2 knockout mice, IL-33 and OVA induced airway hyperresponsiveness and eosinophilic airway inflammation were both completely diminished, and no IL-33/ST2 autoamplification was observed. These results suggest that endogenous IL-33 and its autoamplification of IL-33/ST2 pathway play an important role in the induction of asthma-like phenotype. Thus an intact IL-33/ST2 pathway is necessary for both Ag-dependent and Ag-independent asthma-like mouse models.

中文翻译：

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内源性 IL-33 及其对 IL-33/ST2 通路的自动扩增在哮喘中起重要作用

关键点 IL-33 通过诱导自身和 ST2 表达自动扩增 IL-33/ST2 通路。气道上皮细胞是内源性 IL-33 产生的主要来源。哮喘样小鼠模型需要完整的内源性 IL-33/ST2 通路。IL-33 及其受体 ST2 是导致气道炎症和哮喘恶化的因素。IL-33/ST2 信号通路参与哮喘的发作和急性加重。在这项研究中，我们解决了内源性 IL-33 的作用及其在 Ag 依赖性和 Ag 非依赖性哮喘样模型中 IL-33/ST2 通路的自动扩增。野生型、IL-33 敲除、ST2 敲除小鼠或者连续四天每天气管内施用 500 ng rIL-33，或者用 OVA 致敏和攻击超过 21 天。在野生型小鼠中，IL-33 或 OVA 诱导类似的气道高反应性和嗜酸性气道炎症。IL-33 在肺中诱导其自身的 mRNA 和 ST2L mRNA 表达。IL-33 自身扩增和气道上皮细胞中的 ST2 蛋白表达。OVA 还诱导 IL-33 和 ST2 蛋白表达。在 IL-33 敲除小鼠中，IL-33 和 OVA 诱导的气道高反应性和嗜酸性气道炎症均显着减弱，而 IL-33 诱导的 ST2L mRNA 表达得以保留，尽管没有 IL-33/ST2 通路的自动扩增观察到的。在 ST2 敲除小鼠中，IL-33 和 OVA 诱导的气道高反应性和嗜酸性气道炎症均完全消除，未观察到 IL-33/ST2 自动扩增。这些结果表明内源性 IL-33 及其自身扩增 IL-33/ST2 通路在哮喘样表型的诱导中起重要作用。因此，完整的 IL-33/ST2 通路对于 Ag 依赖性和 Ag 非依赖性哮喘样小鼠模型都是必要的。