Pyroptotic neuronal cell death mediated by the AIM2 inflammasome
Pyroptotic neuronal cell death mediated by the AIM2 inflammasome
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DOI：
10.1038/jcbfm.2013.236
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发表时间：
2014-04-01
影响因子：
6.3
通讯作者：
Keane, Robert W.
中科院分区：
文献类型：
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作者：
Adamczak, Stephanie E.;Vaccari, Juan Pablo de Rivero;Keane, Robert W.
中枢神经系统（CNS）是对感染和损伤的先天免疫应答的积极参与者。在这些研究中，我们发现胚胎皮层神经元表达一种功能性的、脱氧核糖核酸（DNA）响应性的、在黑色素瘤2（AIM 2）炎性小体中不存在的激活半胱天冬酶-1的物质。神经元经历焦亡，这是一种促炎性细胞死亡机制，其特征如下：（a）含有半胱天冬酶募集结构域（ASC）的焦亡相关斑点样蛋白的寡聚化;（B）半胱天冬酶-1依赖性;（c）质膜中离散孔的形成;和（d）炎性细胞因子白细胞介素-β（IL-1 β）的释放。丙磺舒和亮蓝FCF，pannexin 1通道的抑制剂，防止AIM 2炎性小体介导的细胞死亡，确定pannexin 1作为细胞死亡效应在焦亡和丙磺舒作为一种新的焦亡抑制剂。此外，我们显示了创伤性脑损伤（TBI）患者的脑脊液（CSF）和ASC的寡聚化激活神经元中的AIM 2炎性体。这些结果表明，神经元的pyroptosis是一个重要的细胞死亡机制，在中枢神经系统感染和损伤，可减弱丙磺舒。
The central nervous system (CNS) is an active participant in the innate immune response to infection and injury. In these studies, we show embryonic cortical neurons express a functional, deoxyribonucleic acid (DNA)-responsive, absent in melanoma 2 (AIM2) inflammasome that activates caspase-1. Neurons undergo pyroptosis, a proinflammatory cell death mechanism characterized by the following: (a) oligomerization of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC); (b) caspase-1 dependency; (c) formation of discrete pores in the plasma membrane; and (d) release of the inflammatory cytokine interleukin-beta (IL-1 beta). Probenecid and Brilliant Blue FCF, inhibitors of the pannexin1 channel, prevent AIM2 inflammasome-mediated cell death, identifying pannexin1 as a cell death effector during pyroptosis and probenecid as a novel pyroptosis inhibitor. Furthermore, we show activation of the AIM2 inflammasome in neurons by cerebrospinal fluid (CSF) from traumatic brain injury (TBI) patients and oligomerization of ASC. These findings suggest neuronal pyroptosis is an important cell death mechanism during CNS infection and injury that may be attenuated by probenecid.