NLRP3炎性小体与炎症性肠病幻灯片.pptxVIP

NLRP3炎性小体与炎症性肠病的研究进展;;1.引言;NLRP3 炎性小体的活化可致无活性的caspase-1 前体转化为活性caspase-1，后者可裂解白细胞介素（IL-1β）、IL-18、IL-33 前体以形成活性形式并分泌。NLRP3 已证实与人类多种自身免疫病相关，如家族性寒冷自身炎症综合征（familial cold utoinflammatory syndrome,FCAS）、穆-韦综合征（Muckle-Wells syndrome，MWS）和新生儿期多系统炎症综合征（neonatal onset ultisystem inflammatory disease, NOMID）， 上述疾病统称为隐热蛋白-相关周期综合征（cryopyrin associated periodic syndrome, CAPS）。; NLRs;2.NLRP3 Inflamasome;分布;Figure 1. Schematic of NLRP1, NLRP3, NLRC4, and AIM2 inflammasomes. Human NLRP1 can interact with ASC and caspase-1 via an N-terminal PYD and also bind caspase-5 to the complex via the C-terminal CARD. Muramyl dipeptide (MDP), Bacillus anthracis lethal toxin, and Toxoplasma gondii can induce the activation of the NLRP1 inflammasome. Mouse Nlrp1b does not possess a functional N-terminal PYD, hence caspase-1 may interact with its C-terminal CARD. NLRP3 interacts with ASC through an N-terminal PYD domain, which then recruits caspase-1.Mitochondrial DNA (mtDNA) and cardiolipin have been postulated to bind to NLRP3 and induce its activation., nucleotide-binding and oligomerization domain.;激活剂;Figure2. Signals mediating NLRP3 inflammasome priming.Upon engagement, patternrecognition receptors (PRR), such as TLR4 and NOD2, or cytokine receptors, such as TNFR and IL-1R, activate NF-B, leading to the transcription and translation of NLRP3 and pro-IL-1. Dissociation of HSP90 and SGT1 from NLRP3 is required for NLRP3 inflammasome activation. Additionally, NLRP3 undergoes deubiquitylation by the JAMM domain–containing Zn2+ metalloprotease deubiquitinating enzyme BRCC3,which is crucial for subsequent NLRP3 inflammasome activation. Upon activation of the NLRP3 inflammasome, active caspase-1 can process pro-IL-1 and pro-IL-18 into their mature secreted forms.;Figure 3. Inhibition of NLRP3 inflammasome activation. Type I IFNs acting through IFNAR inhibit the transcription of pro-IL-1 through the upregulation of the anti-inflammatory cytokine IL-10. Type I IFNs and IFN- inhibit NLRP3 through