Key Points IL-33 mediates eosinophilic recruitment and Th2 inflammation in Tg+ airways. MUC5AC, not MUC5B, is significantly suppressed in the airways of IL-33KO/Tg+ mice. Mucous cell density, not muco-obstruction, is suppressed in IL-33KO/Tg+ airways. Cystic fibrosis is characterized by dehydration of the airway surface liquid layer with persistent mucus obstruction. Th2 immune responses are often manifested as increased mucous cell density (mucous cell metaplasia) associated with mucus obstruction. IL-33 is a known inducer of Th2 immune responses, but its roles in mucus obstruction and related phenotypes in a cystic fibrosis–like lung disease model (i.e., Scnn1b-Tg–positive [Tg+]) mouse, remain unclear. Accordingly, IL-33 knockout (IL-33KO) Tg+ mice were examined and compared with IL-33 heterozygous (IL-33HET) Tg+ mice. As compared with IL-33HET/Tg+ mice, IL-33KO/Tg+ mice had complete absence of bronchoalveolar lavage fluid eosinophilia, accompanied with significant reduction in bronchoalveolar lavage fluid concentration of IL-5, a cytokine associated with eosinophil differentiation and recruitment, and IL-4, a major Th2 cytokine. As compared with IL-33HET/Tg+ mice, IL-33KO/Tg+ mice had significantly reduced levels of Th2-associated gene signatures (Slc26a4, Clca1, Retnla, and Chi3l4), along with complete loss of intracellular mucopolysaccharide staining in the airway epithelium. As compared with IL-33HET/Tg+ mice, although the IL-33KO/Tg+ mice had significantly reduced levels of MUC5AC protein expression, they showed no reduction in the degree of mucus obstruction, MUC5B protein expression, bacterial burden, and neonatal mortality. Interestingly, the histological features, including subepithelial airway inflammation and alveolar space enlargement, were somewhat exaggerated in IL-33KO/Tg+ mice compared with IL-33HET/Tg+ mice. Taken together, our data indicate that although IL-33 modulates Th2 inflammatory responses and MUC5AC protein production, mucus obstruction is not dependent on IL-33.

中文翻译：

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在 Scnn1b 转基因小鼠模型中，IL-33 的消融抑制 Th2 反应，但伴随着持续的粘液阻塞

关键点 IL-33 介导 Tg+ 气道中的嗜酸性粒细胞募集和 Th2 炎症。MUC5AC，而不是 MUC5B，在 IL-33KO/Tg+ 小鼠的气道中被显着抑制。在 IL-33KO/Tg+ 气道中，黏液细胞密度（而非黏液阻塞）受到抑制。囊性纤维化的特征是气道表面液体层脱水并伴有持续粘液阻塞。Th2 免疫反应通常表现为与粘液阻塞相关的粘液细胞密度增加（粘液细胞化生）。IL-33 是一种已知的 Th2 免疫反应诱导剂，但其在囊性纤维化样肺病模型（即 Scnn1b-Tg 阳性 [Tg+]）小鼠的粘液阻塞和相关表型中的作用仍不清楚。因此，检查了 IL-33 敲除 (IL-33KO) Tg+ 小鼠并与 IL-33 杂合 (IL-33HET) Tg+ 小鼠进行了比较。与 IL-33HET/Tg+ 小鼠相比，IL-33KO/Tg+ 小鼠完全没有支气管肺泡灌洗液嗜酸性粒细胞增多，同时支气管肺泡灌洗液中 IL-5 的浓度显着降低，IL-5 是一种与嗜酸性粒细胞分化和募集相关的细胞因子，以及 IL -4，主要的Th2细胞因子。与 IL-33HET/Tg+ 小鼠相比，IL-33KO/Tg+ 小鼠的 Th2 相关基因特征（Slc26a4、Clca1、Retnla 和 Chi3l4）水平显着降低，同时气道上皮细胞内粘多糖染色完全消失。与 IL-33HET/Tg+ 小鼠相比，虽然 IL-33KO/Tg+ 小鼠的 MUC5AC 蛋白表达水平显着降低，但它们的粘液阻塞程度、MUC5B 蛋白表达、细菌负荷和新生儿死亡率没有降低。有趣的是，与 IL-33HET/Tg+ 小鼠相比，IL-33KO/Tg+ 小鼠的组织学特征，包括上皮下气道炎症和肺泡空间扩大，有些夸大。总之，我们的数据表明，虽然 IL-33 调节 Th2 炎症反应和 MUC5AC 蛋白的产生，但粘液阻塞并不依赖于 IL-33。