Protective role of commensals against Clostridium difficile infection via an IL-1β-mediated positive-feedback loop.
Protective role of commensals against Clostridium difficile infection via an IL-1β-mediated positive-feedback loop.
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DOI：
10.4049/jimmunol.1200821
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发表时间：
2012-09-15
期刊：
影响因子：
--
通讯作者：
Inohara N
中科院分区：
文献类型：
--
作者：
Hasegawa M;Kamada N;Jiao Y;Liu MZ;Núñez G;Inohara N
艰难梭菌（Cd）是一种革兰氏阳性专性厌氧病原体，可导致接受过抗真菌治疗的患者发生伪膜性结肠炎。共生细菌是已知的有一个显着的作用，在肠道积累的镉抗生素治疗后，但鲜为人知的是，它们如何影响宿主的免疫力在镉感染。在这里，我们报告说，镉感染的结果易位的肠道上皮屏障，这是至关重要的中性粒细胞募集通过诱导IL-1β介导的正反馈回路的肠道上皮屏障。ASC是IL-1β和IL-18加工和分泌的重要介质，缺乏ASC的小鼠对Cd感染高度敏感。ASC-/-小鼠表现出增强易位的骨髓到多个器官后，镉感染。值得注意的是，ASC-/-小鼠表现出受损的CXCL 1生产和中性粒细胞流入肠道组织响应镉感染。中性粒细胞募集的受损导致IL-1β和CXCL 1的产生减少，但不导致IL-18的产生减少。重要的是，中性粒细胞分泌ASC/Nlrp 3依赖性IL-1β需要易位的细胞。缺乏IL-1β的小鼠在诱导CXCL 1分泌方面存在缺陷，这表明IL-1β是Cd感染期间ASC介导的CXCL 1产生的主要诱导剂。这些结果表明，易位的细胞通过IL-1β/NLRP 3/ASC介导的正反馈机制在CXCL 1依赖性的中性粒细胞向肠道的募集中起关键作用，该机制对于Cd感染期间宿主存活和易位的细胞的清除是重要的。
Clostridium difficile (Cd) is a Gram-positive obligate anaerobic pathogen that causes pseudomembranous colitis in antibiotic-treated individuals. Commensal bacteria are known to have a significant role in the intestinal accumulation of Cd after antibiotic treatment, but little is known about how they affect host immunity during Cd infection. Here we report that Cd infection results in translocation of commensals across the intestinal epithelial barrier that is critical for neutrophil recruitment through the induction of an IL-1β-mediated positive feedback loop. Mice lacking ASC, an essential mediator of IL-1β and IL-18 processing and secretion, were highly susceptible to Cd infection. ASC−/− mice exhibited enhanced translocation of commensals to multiple organs after Cd infection. Notably, ASC−/− mice exhibited impaired CXCL1 production and neutrophil influx into intestinal tissues in response to Cd infection. The impairment in neutrophil recruitment resulted in reduced production of IL-1β and CXCL1, but not IL-18. Importantly, translocated commensals were required for ASC/Nlrp3-dependent IL-1β secretion by neutrophils. Mice lacking IL-1β were deficient in inducing CXCL1 secretion, suggesting that IL-1β is the dominant inducer of ASC-mediated CXCL1 production during Cd infection. These results indicate that translocated commensals play a crucial role in CXCL1-dependent recruitment of neutrophils to the intestine through an IL-1β/NLRP3/ASC-mediated positive feedback mechanism that is important for host survival and clearance of translocated commensals during Cd infection.
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影响因子：
3.7
作者：
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影响因子：
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影响因子：
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作者：
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