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

志贺氏菌是细菌性痢疾的病原体，称为志贺氏菌病。志贺氏菌致病倾向的一个关键方面在于它能够入侵上皮细胞和巨噬细胞的细胞质。细菌侵入巨噬细胞会导致上睑下垂，即与caspase-1激活相关的前炎性细胞死亡。激活的caspase-1然后裂解和激活前白介素1β和前白介素18，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caspase-1激活的确切机制尚不清楚。IPAF是核苷酸结合寡聚化结构域(NOD)样受体(NLR)家族的一种胞质模式识别受体，是通过感知沙门氏菌或军团菌等细菌产生的鞭毛而激活caspase-1的关键宿主因子。作者发现，非鞭毛志贺氏菌感染诱导的caspase-1激活需要IPAF和接头蛋白ASC。因此，IPAF和ASC通过感知未知细菌因子而不是鞭毛蛋白来介导caspase-1的激活。自噬是一种清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，由于缺乏caspase-1或IPAF而不是ASC，自噬作用显著增强。自噬的抑制促进了志贺氏菌诱导的细胞死亡，表明自噬保护受感染的巨噬细胞免于下垂。本研究提供证据表明，在志贺氏菌感染的巨噬细胞中，IPAF和caspase-1抑制自噬，而ASC正向调节自噬，为NLR蛋白在细菌-宿主相互作用中提供了新的功能。

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.