Pseudomonas aeruginosa Triggers Macrophage Autophagy To Escape Intracellular Killing by Activation of the NLRP3 Inflammasome
Pseudomonas aeruginosa Triggers Macrophage Autophagy To Escape Intracellular Killing by Activation of the NLRP3 Inflammasome
复制标题
铜绿假单胞菌通过激活 NLRP3 炎症小体触发巨噬细胞自噬以逃避细胞内杀伤
DOI：
10.1128/iai.00945-15
复制
发表时间：
2016-01-01
影响因子：
3.1
通讯作者：
Wu, Minhao
中科院分区：
文献类型：
--
作者：
Deng, Qiuchan;Wang, Yi;Wu, Minhao
摘要近年来，炎症小体的组装被认为是炎症发生的关键事件。然而，它在细菌杀灭中的作用尚不清楚。我们的研究表明，铜绿假单胞菌感染可诱导人巨噬细胞NLRP3炎症体的组装以及caspase-1和IL-1β(IL-1β)的顺序分泌。更重要的是，NLRP3炎症体的激活减少了对人巨噬细胞中铜绿假单胞菌的杀灭，而不影响抗菌肽、活性氧物种和一氧化氮的产生。此外，我们的结果表明，铜绿假单胞菌感染增加了人巨噬细胞中LC3-II蛋白的数量，并触发了自噬小体的形成。NLRP3、ASC或caspase1的过表达可增强铜绿假单胞菌诱导的自噬，但下调NLRP3炎症体的这些核心分子可抑制自噬。IL-1β促进人巨噬细胞自噬。更重要的是，IL-1β降低了巨噬细胞介导的对铜绿假单胞菌的杀伤作用，而敲除ATG7或Beclin1则恢复了IL-1β对细菌杀伤的抑制作用。总之，我们的研究探索了铜绿假单胞菌逃避吞噬细胞杀伤的新机制，并可能提供更好的了解铜绿假单胞菌与宿主免疫细胞(包括巨噬细胞)之间的相互作用。
ABSTRACT Assembly of the inflammasome has recently been identified to be a critical event in the initiation of inflammation. However, its role in bacterial killing remains unclear. Our study demonstrates that Pseudomonas aeruginosa infection induces the assembly of the NLRP3 inflammasome and the sequential secretion of caspase1 and interleukin-1β (IL-1β) in human macrophages. More importantly, activation of the NLRP3 inflammasome reduces the killing of P. aeruginosa in human macrophages, without affecting the generation of antimicrobial peptides, reactive oxygen species, and nitric oxide. In addition, our results demonstrate that P. aeruginosa infection increases the amount of the LC3-II protein and triggers the formation of autophagosomes in human macrophages. The P. aeruginosa-induced autophagy was enhanced by overexpression of NLRP3, ASC, or caspase1 but was reduced by knockdown of these core molecules of the NLRP3 inflammasome. Treatment with IL-1β enhanced autophagy in human macrophages. More importantly, IL-1β decreased the macrophage-mediated killing of P. aeruginosa, whereas knockdown of ATG7 or Beclin1 restored the IL-1β-mediated suppression of bacterial killing. Collectively, our study explores a novel mechanism employed by P. aeruginosa to escape from phagocyte killing and may provide a better understanding of the interaction between P. aeruginosa and host immune cells, including macrophages.