Microbial pathogen-induced necrotic cell death mediated by the inflammasome components CIAS1/Cryopyrin/NLRP3 and ASC
Microbial pathogen-induced necrotic cell death mediated by the inflammasome components CIAS1/Cryopyrin/NLRP3 and ASC
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DOI：
10.1016/j.chom.2007.07.009
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发表时间：
2007-09-01
影响因子：
30.3
通讯作者：
Ting, Jenny P. -Y.
中科院分区：
文献类型：
--
作者：
Willingham, Stephen B.;Bergstralh, Daniel T.;Ting, Jenny P. -Y.
Cryopyrin（CIAS 1，NLRP 3）和ASC是炎性小体的组分，炎性小体是半胱天冬酶-1活化和细胞因子IL-1 β产生所需的多蛋白复合物。CIAS 1突变是以过度IL-1 β分泌为特征的自身炎症的基础。疾病相关的cryopyrin也导致巨噬细胞中的坏死样细胞死亡程序，其机制细节尚不清楚。我们发现携带疾病相关CIAS 1突变的患者单核细胞通过依赖于ASC和组织蛋白酶B的过程表现出过度的坏死样死亡，导致促炎介质HMG 1的溢出。福氏志贺菌感染也引起cryopyrin依赖性巨噬细胞坏死，其特征类似于突变体CIAS 1引起的死亡。这种坏死性死亡不依赖于半胱天冬酶-1和IL-1 β，因此不依赖于炎性小体。此外，原代巨噬细胞的坏死需要志贺氏菌毒力基因的存在。虽然类似的蛋白质介导的病原体诱导的细胞死亡的植物，本报告确定cryopyrin作为一个重要的主机调节程序病原体诱导的坏死在动物中，一个过程，我们术语的pyronecrosis。
Cryopyrin (CIAS1, NLRP3) and ASC are components of the inflammasome, a multiprotein complex required for caspase-1 activation and cytokine IL-1 beta production. CIAS1 mutations underlie autoinflammation characterized by excessive IL-1 beta secretion. Disease-associated cryopyrin also causes a program of necrosis-like cell death in macrophages, the mechanistic details of which are unknown. We find that patient monocytes carrying disease-associated CIAS1 mutations exhibit excessive necrosis-like death by a process dependent on ASC and cathepsin B, resulting in spillage of the proinflammatory mediator HMGB1. Shigella flexneri infection also causes cryopyrin-dependent macrophage necrosis with features similar to the death caused by mutant CIAS1. This necrotic death is independent of caspase-1 and IL-1 beta, and thus independent of the inflammasome. Furthermore, necrosis of primary macrophages requires the presence of Shigella virulence genes. While similar proteins mediate pathogen-induced cell death in plants, this report identifies cryopyrin as an important host regulator of programmed pathogen-induced necrosis in animals, a process we term pyronecrosis.