Inflammasome
根据亚细胞定位的不同,PRRs 主要被分成两类。第一类Toll 样受体(Toll-like receptors,TLRs)和C 型凝集素受体(C-type lectin receptors,CLRs)是跨膜蛋白,定位于质膜和内体中,能够识别细胞外基质中的PAMPs 与DAMPs。第二类PRRs 是细胞内组分中包括RIG-I 样受体(RIG-I-like receptor,RLRs)、AIM2 样受体(AIM2-like receptors,ALRs)、NOD样受体(NOD-like receptors,NLRs)和细胞内DNA 的感受器(DNA sensors)[3-4] 。许多PRRs 识别PAMPs 和DAMPs 后,通过核因子κB(nuclear factor-κB,NF-κB)、激活蛋白(activator protein 1,AP1)和干扰素调节因子(interferon regulatory factors,IRFs)来激活信号分子,最终促进细胞因子、干扰素、促炎因子和微生物杀伤蛋白的释放.
而一些NLRs 和ALRs则采取不同的防御机制,这些蛋白装配出细胞内被叫做炎症小体(inflammasome)的蛋白复合体,促进半胱氨酸天冬氨酸特异性蛋白水解酶前体(pro-cysteinyl aspartate specific proteinase,procaspase)-1 和procaspase-11 蛋白酶[5-6] ,迅速使其转化成活化的caspase-1 和caspase-11,最终导致:(1)白细胞介素(interleukin,IL)-1β 和IL-18 的产生;(2)细胞焦亡(pyronecrosis)。
经典炎症小体( canonical inflammasomes) 催化procaspase-1 进入酶激活状态,而并没有被定义的非经典炎症小体(non-canonical inflammasomes) 则促进procaspase-11 的激活。炎症小体通过诱导细胞焦亡和分泌炎症因子IL-1β 和IL-18 调节宿主抵抗反应。细胞焦亡是非稳态和溶菌性的细胞死亡模式,依赖于caspase-1 和caspase-11 的激活。caspase-1 和caspase-11 都能够诱导细胞焦亡,但是只有caspase-1 促进IL-1β 和IL-18 的分泌。IL-1β 和IL-18 都是非常重要的炎症效应因子。
已发现的炎性小体主要有5种，即NLRP1炎性小体、NLRP3炎性小体、NLRC4炎性小体、IPAF炎性小体和AIM2/IFI16炎性小体以及non-canonical inflammasomes。
Inflammasomes are cytosolic multiprotein oligomers of the innate immune system responsible for the activation of inflammatory responses.[1][2] Activation and assembly of the inflammasome promotes proteolytic cleavage, maturation and secretion of pro-inflammatory cytokines interleukin 1β (IL-1β) and interleukin 18 (IL-18), as well as cleavage of Gasdermin-D.[2][3] The N-terminal fragment resulting from this cleavage induces a pro-inflammatory form of programmed cell death distinct from apoptosis, referred to as pyroptosis, and is responsible for secretion of the mature cytokines, presumably through the formation of pores in the plasma membrane.[2] In the case of dysregulation of inflammasome activation, an assortment of major diseases, such as cancer, autoimmune, metabolic and neurodegenerative diseases may arise.[2][4]
Traditionally, inflammasomes have mainly been studied in professional immune cells of the innate immune system, such as macrophages. More recent studies, however, indicate high levels of inflammasome component expression in epithelial barrier tissues, where they have been shown represent an important first line of defense.[5] Inflammasome activation is initiated by different kinds of cytosolic pattern recognition receptors (PRRs) that respond to either microbe-derived pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs) generated by the host cell.[5] Pattern recognition receptors involved in inflammasomes comprise NLRs (nucleotide-binding oligomerization domain and leucine-rich repeat-containing receptors) as well as AIM2 (absent in melanoma 2), IFI16 (IFN-inducible protein 16 ) as well as pyrin.[2]
Through their caspase activation and recruitment domain (CARD) or pyrin domain (PYD), the inflammasome receptors interact with the adaptor protein ASC, which then recruits pro-caspase-1 via its CARD domain and activates the effector caspase through proteolytic cleavage.[2] The activated caspase-1 finally cleaves the immature pro-inflammatory cytokines pro-IL-1β and pro-IL-18, as well as Gasdermin-D, which are responsible for inflammatory signaling and pyroptotic cell death, respectively.[2] In addition to these so-called canonical inflammasomes, different studies also described non-canonical inflammasome complexes that act independently of caspase-1. In mice, the non-canonical inflammasome is activated by direct sensing of cytosolic bacterial lipopolysaccharide (LPS) by caspase-11, which subsequently induces pyroptotic cell death.[2] In human cells, the corresponding caspases of the non-canonical inflammasome are caspase 4 and caspase 5.