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Molecular mechanisms of cell death and inflammatory responses of antigen presenting cells upon infection of mucosal pathogenic bacteria

粘膜病原菌感染后抗原呈递细胞细胞死亡和炎症反应的分子机制

基本信息

批准号：
18390133
负责人：
SUZUKI Toshihiko
金额：
$ 10.5万
依托单位：
University of the Ryukyus
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18390133/
关键词：
Shigella macrophages cell death inflammation

项目摘要

Shigella are bacterial pathogens that are the cause of bacillary dysentery known as shigellosis. A crucial aspect of the propensity of Shigella to cause diseases lies in its ability to invade into the cytoplasm of epithelial cells as well as macrophages. The bacterial invasion into macrophages induces pyroptosis, the proinflammatory cell death associated with caspase-1 activation. Activated caspase-1 then cleaves and activates prointerleukin (IL)-1β and proIL-18 that are proinflammatory cytokines involved in host inflammatory responses. However, the precise mechanisms of caspase-1 activation induced by Shigella infection remain poorly understood. Ipaf, a cytosolic pattern-recognition receptor of the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family is a crucial host factor to activate caspase-1 through the sensing of flagellin produced by some bacteria such as Salmonella or Legionella. The authors discovered that Ipaf and the adaptor protein ASC are required for caspase-1 activation induced by non-flagellated Shigella infection. Thus Ipaf and ASC mediate caspase-1 activation by sensing unknown bacterial factor but not flagellin. Autophagy, a cellular system for eliminating intracellular pathogens, was dramatically enhanced in Shigella-infected macrophages by the absence of caspase-1 or Ipaf, but not ASC. The inhibition of autophagy promoted Shigella-induced cell death, suggesting that autophagy protects infected macrophages from pyroptosis. This study provides evidence that in Shigella-infected macrophages, autophagy is inhibited by Ipaf and caspase-1, whereas positively regulated by ASC, providing a novel function for NLR proteins in bacterial-host interactions.

志贺氏菌是细菌病原体，是细菌性痢疾的原因，称为志贺氏菌病。志贺氏菌致病倾向的一个重要方面在于它能够侵入上皮细胞和巨噬细胞的细胞质。细菌侵入巨噬细胞诱导焦亡，这是与半胱天冬酶-1活化相关的促炎细胞死亡。活化的半胱天冬酶-1然后切割并活化白细胞介素（IL）-1β和IL-18原，它们是参与宿主炎症反应的促炎细胞因子。然而，志贺氏菌感染诱导的caspase-1激活的确切机制仍然知之甚少。Ipaf是核苷酸结合寡聚化结构域（NOD）样受体（NLR）家族的胞浆模式识别受体，是通过感测某些细菌（例如沙门氏菌或军团菌）产生的鞭毛蛋白来激活caspase-1的关键宿主因子。作者发现Ipaf和衔接蛋白ASC是由非鞭毛志贺氏菌感染诱导的caspase-1活化所必需的。因此，Ipaf和ASC通过感应未知细菌因子而不是鞭毛蛋白介导半胱天冬酶-1活化。自噬是一种消除细胞内病原体的细胞系统，在志贺氏菌感染的巨噬细胞中，caspase-1或Ipaf的缺乏显著增强，但ASC不增强。自噬的抑制促进志贺氏菌诱导的细胞死亡，表明自噬保护感染的巨噬细胞免于焦亡。这项研究提供的证据表明，在志贺氏菌感染的巨噬细胞中，自噬被Ipaf和caspase-1抑制，而ASC正调控，为NLR蛋白在细菌-宿主相互作用中提供了一种新的功能。