Pulmonary Regnase-1 orchestrates the interplay of epithelium and adaptive immune systems to protect against pneumonia
Pulmonary Regnase-1 orchestrates the interplay of epithelium and adaptive immune systems to protect against pneumonia
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DOI：
10.1038/s41385-018-0024-5
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发表时间：
2018-04
影响因子：
8
通讯作者：
Y. Nakatsuka;A. Vandenbon;Takashi Mino;Masanori Yoshinaga;Takuya Uehata;X. Cui;A. Sato;T. Tsujimura;Yutaka Suzuki;A. Sato;T. Handa;K. Chin;T. Sawa;T. Hirai;O. Takeuchi
中科院分区：
文献类型：
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作者：
Y. Nakatsuka;A. Vandenbon;Takashi Mino;Masanori Yoshinaga;Takuya Uehata;X. Cui;A. Sato;T. Tsujimura;Yutaka Suzuki;A. Sato;T. Handa;K. Chin;T. Sawa;T. Hirai;O. Takeuchi
包括铜绿假单胞菌在内的吸入性病原体会与呼吸道上皮细胞(AECs)相遇，AECs可能会激发细胞固有的天然防御，影响第二层造血细胞介导的免疫反应。然而，各种免疫细胞介导的肺免疫反应是如何协调的，在很大程度上还不清楚。在这里，我们证明了Regnase-1，一种在血管内皮细胞和免疫细胞中表达的内切核酸酶，在协调先天反应和针对P的获得性免疫中起着重要作用。铜绿假单胞菌。气管内给药对热致死小鼠的影响。铜绿假单胞菌导致Regnase-1长时间消失，与Regnase-1靶向炎症基因的持续表达一致，而转录因子NF-κB仅短暂激活。AEC特异性删除Regnase-1不仅增强了对P的天然防御。铜绿假单胞菌还可促进肺炎假单胞菌特异性IgA的分泌和Th17在肺中的积累，最终导致对铜绿假单胞菌产生显著的耐药性。铜绿假单胞菌-体内感染。虽然Regnase-1直接控制每个AEC和T细胞中不同的基因集，但两种细胞中Regnase-1的降解有利于最大化获得性免疫反应。总之，这些结果表明，Regnase-1协调了AEC和免疫细胞介导的宿主对肺部细菌感染的防御。
Inhaled pathogens includingPseudomonas aeruginosainitially 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 againstP. aeruginosainfection. Intratracheal treatment of mice with heat-killedP. aeruginosaresulted 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 againstP. aeruginosabut also enhanced secretion ofPseudomonas-specific IgA and Th17 accumulation in the lung, culminating in conferring significant resistance againstP. aeruginosare-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.