Caspase-8 Blocks Kinase RIPK3-Mediated Activation of the NLRP3 Inflammasome
Caspase-8 Blocks Kinase RIPK3-Mediated Activation of the NLRP3 Inflammasome
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DOI：
10.1016/j.immuni.2012.09.015
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发表时间：
2013-01-24
期刊：
影响因子：
32.4
通讯作者：
Wallach, David
中科院分区：
文献类型：
--
作者：
Kang, Tae-Bong;Yang, Seung-Hoon;Wallach, David
某些细胞中的半胱天冬酶-8缺乏会引起慢性炎症。一种机制被认为是这种炎症的原因，是由caspase-8可以切割的蛋白激酶RIPK 1和RIPK 3介导的坏死细胞死亡的信号增强。我们描述了树突状细胞中caspase-8的活性，其以另一种方式控制炎症的起始。这些细胞中的半胱天冬酶-8缺陷促进了脂多糖诱导的NLRP 3炎性体的组装和功能。这种作用依赖于RIPK 1和RIPK 3以及MLKL和PGAM 5的功能，这两种信号蛋白最近被证明有助于RIPK 3介导的坏死诱导。然而，尽管caspase-8缺陷细胞中炎性小体组装的增强与坏死的诱导共享近端信号事件，但它的发生独立于细胞死亡。这些发现为RIPK 1和RIPK 3介导的信号传导所促成的潜在病理性炎症过程提供了新的见解。
Caspase-8 deficiency in certain cells prompts chronic inflammation. One mechanism suggested to account for this inflammation is enhanced signaling for necrotic cell death, mediated by the protein kinases RIPK1 and RIPK3 that caspase-8 can cleave. We describe an activity of caspase-8 in dendritic cells that controls the initiation of inflammation in another way. Caspase-8 deficiency in these cells facilitated lipopolysaccharide-induced assembly and function of the NLRP3 inflammasome. This effect depended on the functions of RIPK1 and RIPK3, as well as of MLKL and PGAM5, two signaling proteins recently shown to contribute to RIPK3-mediated induction of necrosis. However, although enhancement of inflammasome assembly in the caspase-8-deficient cells shares proximal signaling events with the induction of necrosis, it occurred independently of cell death. These findings provide new insight into potentially pathological inflammatory processes to which RIPK1- and RIPK3-mediated signaling contributes.