Role of Inflammasomes in Host Defense against Citrobacter rodentium Infection
Role of Inflammasomes in Host Defense against Citrobacter rodentium Infection
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DOI：
10.1074/jbc.m112.358705
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发表时间：
2012-05-11
影响因子：
4.8
通讯作者：
Kanneganti, Thirumala-Devi
中科院分区：
文献类型：
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作者：
Liu, Zhiping;Zaki, Md Hasan;Kanneganti, Thirumala-Devi
鼠柠檬酸杆菌是小鼠肠道的一种肠道细菌病原体，它引发的炎症反应类似于感染肠致病性和肠出血性大肠杆菌的人类的炎症反应。炎症小体信号传导正在成为对几种病原体的炎症和宿主反应的核心调节因子，但炎症小体信号传导在宿主防御鼠柠檬酸杆菌中的体内作用尚未得到表征。在此，我们表明缺乏炎症小体成分Nlrp3、Nlrc4和半胱天冬酶 - 1的小鼠对鼠柠檬酸杆菌诱导的胃肠道炎症高度易感。这是由于白细胞介素（IL）-1β和IL - 18产生缺陷，因为il - 1β（-/-）和il - 18（-/-）小鼠也遭受细菌负荷增加和组织病理学恶化。鼠柠檬酸杆菌在体外感染的巨噬细胞中特异性激活Nlrp3炎症小体，且不依赖于功能性细菌III型分泌系统。因此，Nlrp3和Nlrc4炎症小体下游的IL - 1β和IL - 18的产生在宿主防御鼠柠檬酸杆菌引起的肠道感染中起关键作用。
Citrobacter rodentium is an enteric bacterial pathogen of the mouse intestinal tract that triggers inflammatory responses resembling those of humans infected with enteropathogenic and enterohemorrhagic Escherichia coli. Inflammasome signaling is emerging as a central regulator of inflammatory and host responses to several pathogens, but the in vivo role of inflammasome signaling in host defense against C. rodentium has not been characterized. Here, we show that mice lacking the inflammasome components Nlrp3, Nlrc4, and caspase-1 were hypersusceptible to C. rodentium-induced gastrointestinal inflammation. This was due to defective interleukin (IL)-1 beta and IL-18 production given that il-1 beta(-/-) and il-18(-/-) mice also suffered from increased bacterial burdens and exacerbated histopathology. C. rodentium specifically activated the Nlrp3 inflammasome in in vitro-infected macrophages independently of a functional bacterial type III secretion system. Thus, production of IL-1 beta and IL-18 downstream of the Nlrp3 and Nlrc4 inflammasomes plays a critical role in host defense against enteric infections caused by C. rodentium.