Key Points The innate lymphoid system promotes bacterial clearance from airspaces. The innate lymphoid system mediates Th2 responses in the Tg+ airspaces. Ablation of the innate lymphoid system abolishes MCM in the Tg+ airspaces. Innate lymphoid and adaptive immune cells are known to regulate epithelial responses, including mucous cell metaplasia (MCM), but their roles in mucoinflammatory airway diseases, such as cystic fibrosis, remain unknown. Scnn1b transgenic (Scnn1b-Tg+) mice, which recapitulate cystic fibrosis–like mucoinflammatory airway disease, deficient in innate lymphoid (Il2rg knockout mice [Il2rgKO]), adaptive immune (Rag1 knockout mice [Rag1KO]), or both systems (Il2rgKO/Rag1KO), were employed to investigate their respective contributions in the pathogenesis of mucoinflammatory airway disease. As previously reported, immunocompetent Tg+ juveniles exhibited spontaneous neonatal bacterial infections with robust mucoinflammatory features, including elevated expression of Th2-associated markers accompanied by MCM, elevated MUC5B expression, and airway mucus obstruction. The bacterial burden was increased in Il2rgKO/Tg+ juveniles but returned to significantly lower levels in Il2rgKO/Rag1KO/Tg+ juveniles. Mechanistically, this improvement reflected reduced production of adaptive immunity-derived IL-10 and, in turn, increased activation of macrophages. Although all the mucoinflammatory features were comparable between the immunocompetent Tg+ and Rag1KO/Tg+ juveniles, the Il2rgKO/Tg+ and Il2rgKO/Rag1KO/Tg+ juveniles exhibited suppressed expression levels of Th2 markers, diminished MCM, suppressed MUC5B expression, and reduced mucus obstruction. Collectively, these data indicate that, in the context of airway mucus obstruction, the adaptive immune system suppresses antibacterial macrophage activation, whereas the innate lymphoid system contributes to MCM, mucin production, and mucus obstruction.

中文翻译：

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先天淋巴系统是小鼠粘膜炎性气道疾病表现的关键参与者

关键点先天淋巴系统促进细菌从空气空间清除。先天淋巴系统介导 Tg+ 空域中的 Th2 反应。先天淋巴系统的消融消除了 Tg+ 空域中的 MCM。已知先天淋巴样和适应性免疫细胞可调节上皮反应，包括粘液细胞化生 (MCM)，但它们在粘膜炎性气道疾病（如囊性纤维化）中的作用仍然未知。Scnn1b 转基因 (Scnn1b-Tg+) 小鼠，重现囊性纤维化样粘膜炎性气道疾病，缺乏先天淋巴系统（Il2rg 敲除小鼠 [Il2rgKO]）、适应性免疫（Rag1 敲除小鼠 [Rag1KO]）或两种系统（Il2rgKO/Rag1KO） )，被用来研究它们各自在粘膜炎性气道疾病的发病机制中的贡献。正如之前报道的那样，具有免疫活性的 Tg+ 幼鱼表现出具有强烈黏液炎症特征的自发性新生儿细菌感染，包括伴有 MCM 的 Th2 相关标志物表达升高、MUC5B 表达升高和气道粘液阻塞。Il2rgKO/Tg+ 幼鱼的细菌负荷增加，但 Il2rgKO/Rag1KO/Tg+ 幼鱼的细菌负荷显着降低。从机制上讲，这种改善反映了适应性免疫衍生的 IL-10 的产生减少，进而增加了巨噬细胞的活化。尽管免疫活性 Tg+ 和 Rag1KO/Tg+ 幼鱼的所有黏液炎症特征都具有可比性，但 Il2rgKO/Tg+ 和 Il2rgKO/Rag1KO/Tg+ 幼鱼表现出 Th2 标志物表达水平受到抑制、MCM 减少、MUC5B 表达抑制和粘液阻塞减少。总的来说，