NLRP6 negatively regulates innate immunity and host defence against bacterial pathogens.
NLRP6 negatively regulates innate immunity and host defence against bacterial pathogens.
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DOI：
10.1038/nature11250
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发表时间：
2012-08-16
期刊：
影响因子：
64.8
通讯作者：
Kanneganti, Thirumala-Devi
中科院分区：
文献类型：
--
作者：
Anand, Paras K.;Malireddi, R. K. Subbarao;Lukens, John R.;Vogel, Peter;Bertin, John;Lamkanfi, Mohamed;Kanneganti, Thirumala-Devi
细胞内核苷酸结合和寡聚化结构域样受体家族的成员通过激活NF-κB、I型干扰素和炎症体信号来促进免疫反应。最近研究表明，缺乏NLRP6家族成员的小鼠易患结肠炎和结直肠肿瘤，但NLRP6在微生物感染中的作用以及NLRP6调控的炎症信号通路的性质尚不清楚。在这里，我们发现NLRP6基因缺陷的小鼠对单核细胞增生性李斯特氏菌、鼠伤寒沙门氏菌和大肠杆菌具有高度的抵抗力。感染NLRP6基因缺陷的小鼠循环中单核细胞和中性粒细胞数量增加，造血细胞和抗辐射细胞中的NLRP6信号有助于增加易感性。在体外，NLRP6缺乏可增强TLRMAPK和典型的NF-κB的激活，但不能促进胞浆NOD1/2结扎。因此，感染NLRP6基因缺陷的细胞产生高水平的NF-κB和MAPK依赖的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因子，并证明了该NLR在阻止革兰氏阳性和阴性细菌病原体清除方面的作用。
Members of the intracellular nucleotide-binding and oligomerization domain (NOD)-like receptor (NLR) family contribute to immune responses through activation of NF-κB, type I interferon and inflammasome signaling. 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 signaling pathways regulated by NLRP6 remain unclear. Here, we show that Nlrp6-deficient mice were 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 signaling in both hematopoietic and radio-resistant cells contributed to increased susceptibility. Nlrp6-deficiency enhanced activation of MAPK and canonical NF-κB upon TLR, but not cytosolic NOD1/2 ligation in vitro. Consequently, infected Nlrp6-deficient cells produced elevated levels of NF-κB- and MAPK-dependent cytokines and chemokines. Thus, our results reveal NLRP6 as a negative regulator of inflammatory signaling, and demonstrate a role for this NLR in impeding clearance of both Gram-positive and –negative bacterial pathogens.
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DOI：
10.1038/nri2851
发表时间：
2010-10
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
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影响因子：
32.4
作者：
Zaki MH;Boyd KL;Vogel P;Kastan MB;Lamkanfi M;Kanneganti TD
通讯作者：
Kanneganti TD
影响因子：
4.8
作者：
Anand, Paras K.;Tait, Stephen W. G.;Kanneganti, Thirumala-Devi
通讯作者：
Kanneganti, Thirumala-Devi
影响因子：
30.5
作者：
Franchi, Luigi;Amer, Amal;Nunez, Gabriel
通讯作者：
Nunez, Gabriel
影响因子：
11.8
作者：
Scallan E;Hoekstra RM;Angulo FJ;Tauxe RV;Widdowson MA;Roy SL;Jones JL;Griffin PM
通讯作者：
Griffin PM