An overview of the non-canonical inflammasome.

An overview of the non-canonical inflammasome.
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DOI:
10.1016/j.mam.2020.100924
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发表时间:
2020-12
影响因子:
10.6
通讯作者:
Stehlik C
Stehlik C
中科院分区:
医学1区
文献类型:
--
作者:
Downs KP;Nguyen H;Dorfleutner A;Stehlik C

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炎症小体是响应感染和细胞应激而组装的大型胞质多蛋白复合物,对于炎症半胱天冬酶的激活以及随后的促炎介质的加工和释放至关重要。虽然 caspase-1 在经典炎症体内被激活,但相关的 caspase-4(在小鼠中也称为 caspase-11)和 caspase-5 在感测到来自革兰氏阴性细菌的胞质脂多糖 (LPS) 后,在非经典炎症体内被激活。然而,典型和非典型炎症小体激活的后果是相似的。 Caspase-1 促进促炎细胞因子白细胞介素 (IL)-1β 和 IL-18 的加工和释放以及危险信号的释放,以及称为细胞焦亡的裂解形式的细胞死亡,而 caspase-4、caspase-5 和 caspase-11 通过裂解成孔蛋白gasdermin D (GSDMD) 直接促进焦亡, 并触发经典 NLRP3 炎性体的二次激活以释放细胞因子。由于非典型炎症小体激活剂 LPS 的存在会导致内毒素血症和败血症,因此非典型炎症小体激活和调节具有重要的临床影响。在这里,我们讨论非典型炎症小体激活的机制、调节其活性的机制及其对健康和疾病的贡献。
Inflammasomes are large cytosolic multiprotein complexes assembled in response to infection and cellular stress, and are crucial for the activation of inflammatory caspases and the subsequent processing and release of pro-inflammatory mediators. While caspase-1 is activated within the canonical inflammasome, the related caspase-4 (also known as caspase-11 in mice) and caspase-5 are activated within the non-canonical inflammasome upon sensing of cytosolic lipopolysaccharide (LPS) from Gram-negative bacteria. However, the consequences of canonical and non-canonical inflammasome activation are similar. Caspase-1 promotes the processing and release of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18 and the release of danger signals, as well as a lytic form of cell death called pyroptosis, whereas caspase-4, caspase-5 and caspase-11 directly promote pyroptosis through cleavage of the pore-forming protein gasdermin D (GSDMD), and trigger a secondary activation of the canonical NLRP3 inflammasome for cytokine release. Since the presence of the non-canonical inflammasome activator LPS leads to endotoxemia and sepsis, non-canonical inflammasome activation and regulation has important clinical ramifications. Here we discuss the mechanism of non-canonical inflammasome activation, mechanisms regulating its activity and its contribution to health and disease.
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