Department of Immunology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA.
Nature. 2012 Aug 16;488(7411):389-93. doi: 10.1038/nature11250.
Members of the intracellular nucleotide-binding and oligomerization domain (NOD)-like receptor (NLR) family contribute to immune responses through activation of nuclear factor-κB (NF-κB), type I interferon and inflammasome signalling. Mice lacking the NLR family member NLRP6 were recently shown to be susceptible to colitis and colorectal tumorigenesis, but the role of NLRP6 in microbial infections and the nature of the inflammatory signalling pathways regulated by NLRP6 remain unclear. Here we show that Nlrp6-deficient mice are highly resistant to infection with the bacterial pathogens Listeria monocytogenes, Salmonella typhimurium and Escherichia coli. Infected Nlrp6-deficient mice had increased numbers of monocytes and neutrophils in circulation, and NLRP6 signalling in both haematopoietic and radioresistant cells contributed to increased susceptibility. Nlrp6 deficiency enhanced activation of mitogen-activated protein kinase (MAPK) and the canonical NF-κB pathway after Toll-like receptor ligation, but not cytosolic NOD1/2 ligation, in vitro. Consequently, infected Nlrp6-deficient cells produced increased levels of NF-κB- and MAPK-dependent cytokines and chemokines. Thus, our results reveal NLRP6 as a negative regulator of inflammatory signalling, and demonstrate a role for this NLR in impeding clearance of both Gram-positive and -negative bacterial pathogens.
细胞内核苷酸结合和寡聚结构域（NOD）样受体（NLR）家族的成员通过激活核因子-κB（NF-κB）、I 型干扰素和炎性小体信号通路来促进免疫反应。最近研究表明，缺乏 NLR 家族成员 NLRP6 的小鼠易患结肠炎和结直肠肿瘤发生，但 NLRP6 在微生物感染中的作用以及 NLRP6 调节的炎症信号通路的性质仍不清楚。在这里，我们表明 Nlrp6 缺陷型小鼠对李斯特菌、鼠伤寒沙门氏菌和大肠杆菌等细菌病原体的感染具有高度抗性。感染 Nlrp6 缺陷型小鼠的循环中有更多的单核细胞和中性粒细胞，造血细胞和放射抗性细胞中的 NLRP6 信号均有助于增加易感性。Nlrp6 缺陷型小鼠在体外经 Toll 样受体配体结合后，丝裂原活化蛋白激酶（MAPK）和经典 NF-κB 通路的激活增强，但细胞质 NOD1/2 配体结合后无此现象。因此，受感染的 Nlrp6 缺陷型细胞产生了更高水平的 NF-κB 和 MAPK 依赖性细胞因子和趋化因子。因此，我们的结果揭示了 NLRP6 作为炎症信号的负调节剂，并证明了该 NLR 在阻碍革兰氏阳性和阴性细菌病原体清除方面的作用。
