Inhaled pathogens including Pseudomonas aeruginosa initially encounter airway epithelial cells (AECs), which are poised to evoke cell-intrinsic innate defense, affecting second tier of hematopoietic cell-mediated immune reaction. However, it is largely unknown how pulmonary immune responses mediated by a variety of immune cells are coordinated. Here we show that Regnase-1, an endoribonuclease expressed in AECs and immune cells, plays an essential role in coordinating innate responses and adaptive immunity against P. aeruginosa infection. Intratracheal treatment of mice with heat-killed P. aeruginosa resulted in prolonged disappearance of Regnase-1 consistent with sustained expression of Regnase-1 target inflammatory genes, whereas the transcription factor NF-κB was only transiently activated. AEC-specific deletion of Regnase-1 not only augmented innate defenses against P. aeruginosa but also enhanced secretion of Pseudomonas-specific IgA and Th17 accumulation in the lung, culminating in conferring significant resistance against P. aeruginosa re-infection in vivo. Although Regnase-1 directly controls distinct sets of genes in each of AECs and T cells, degradation of Regnase-1 in both cell types is beneficial for maximizing acquired immune responses. Collectively, these results demonstrate that Regnase-1 orchestrates AEC-mediated and immune cell-mediated host defense against pulmonary bacterial infection.

中文翻译：

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肺 Regnase-1 协调上皮细胞和适应性免疫系统的相互作用以预防肺炎。

包括铜绿假单胞菌在内的吸入病原体最初会遇到气道上皮细胞 (AEC)，这些细胞准备激发细胞内在的先天防御，影响造血细胞介导的第二层免疫反应。然而，由多种免疫细胞介导的肺部免疫反应是如何协调的在很大程度上是未知的。在这里，我们表明 Regnase-1 是一种在 AEC 和免疫细胞中表达的核糖核酸内切酶，在协调针对铜绿假单胞菌感染的先天反应和适应性免疫中起着重要作用。用热灭活的铜绿假单胞菌对小鼠进行气管内处理导致 Regnase-1 的长时间消失与 Regnase-1 靶炎症基因的持续表达一致，而转录因子 NF-κB 仅被短暂激活。AEC 特异性缺失 Regnase-1 不仅增强了对铜绿假单胞菌的先天防御能力，而且还增强了假单胞菌特异性 IgA 的分泌和肺中 Th17 的积累，最终在体内赋予了对铜绿假单胞菌再感染的显着抵抗力。尽管 Regnase-1 直接控制每个 AEC 和 T 细胞中不同的基因组，但两种细胞类型中 Regnase-1 的降解有利于最大化获得性免疫反应。总的来说，这些结果表明 Regnase-1 协调 AEC 介导和免疫细胞介导的宿主防御肺部细菌感染。尽管 Regnase-1 直接控制每个 AEC 和 T 细胞中不同的基因组，但两种细胞类型中 Regnase-1 的降解有利于最大化获得性免疫反应。总的来说，这些结果表明 Regnase-1 协调 AEC 介导和免疫细胞介导的宿主防御肺部细菌感染。尽管 Regnase-1 直接控制每个 AEC 和 T 细胞中不同的基因组，但两种细胞类型中 Regnase-1 的降解有利于最大化获得性免疫反应。总的来说，这些结果表明 Regnase-1 协调 AEC 介导和免疫细胞介导的宿主防御肺部细菌感染。