Toll-like receptors activate programmed necrosis in macrophages through a receptor-interacting kinase-3-mediated pathway
Toll-like receptors activate programmed necrosis in macrophages through a receptor-interacting kinase-3-mediated pathway
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Toll 样受体通过受体相互作用激酶 3 介导的途径激活巨噬细胞中的程序性坏死
DOI：
10.1073/pnas.1116302108
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发表时间：
2011-12-13
影响因子：
11.1
通讯作者：
Wang, Xiaodong
中科院分区：
文献类型：
--
作者：
He, Sudan;Liang, Yuqiong;Wang, Xiaodong
我们在这里报道，当toll样受体（TLR） 3和4分别被poly（I: C）和LPS激活时，小鼠巨噬细胞发生受体相互作用激酶-3 （RIP3）依赖但tnf - α独立的坏死。一种适配器蛋白，Toll/IL-1受体结构域适配器诱导ifn - β (TRIF/TICAM-1)，是tnf - α诱导的坏死所必需的，在TLR3/TLR4激活后与RIP3形成复合物，是TLR3/TLR4诱导的坏死所必需的。没有RIP3或功能性TRIF的小鼠暴露于LPS时没有巨噬细胞丢失和炎症细胞因子升高。TNFR或TLR3/TLR4诱导的小鼠巨噬细胞坏死是由活性氧引起的。综上所述，这些数据表明，在哺乳动物对病毒和细菌感染的先天免疫反应中，有多种上游坏死启动信号通路聚集在RIP3上。
We report here that mouse macrophages undergo receptor-interacting kinase-3 (RIP3)-dependent but TNF-alpha-independent necrosis when Toll-like receptors (TLR) 3 and 4 are activated by poly(I: C) and LPS, respectively. An adaptor protein, Toll/IL-1 receptor domain-containing adapter inducing IFN-beta (TRIF/TICAM-1), which is dispensable for TNF-alpha-induced necrosis, forms a complex with RIP3 upon TLR3/TLR4 activation and is essential for TLR3/TLR4-induced necrosis. Mice without RIP3 or functional TRIF did not show macrophage loss and elevation of inflammatory cytokines when they were exposed to LPS. Necrosis in mouse macrophages induced by either TNFR or TLR3/TLR4 is executed by reactive oxygen species. Taken together, these data indicate that there are multiple upstream necrosis-initiating signaling pathways converging on the RIP3 during an innate immune response to viral and bacterial infections in mammals.