文档介绍：NLRP3炎性小体与炎症性肠病的研究进展
主讲人:马娜
导师:冯百岁教授
IBD
PAMPs/DAMPs与PRRs(TLRs/NLRs)
NF-κB通路
炎性小体(*NLRs/ASC/Caspase/AIM2)
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
N-terminal 效应区含有一个热蛋白结构域(PYD), caspase招募结构域(CARD), 或一个杆状病毒凋亡抑制重复结构域(BIR),NLRs亚类的分类依据(NLRA/NLRB/NLRC/NLRP/NLRX)。
Central 核苷酸结合寡聚化结构域(NACHT),是各种NLRs的共同特征。
C-terminus 亮氨酸重复区(LRR)
Inflamasome
distribution
Structure
Mechanisms of its activation
Signal1:Priming
Signal2:Activation
Inhibition
function
分布
NLRP3 在中性粒细胞、单核细胞、淋巴细胞、树突细胞、成骨细胞、上皮细胞(口咽部、食管、外宫颈、尿道)、皮肤角质形成细胞等均有表达。
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 plex 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- DNA (mtDNA) and cardiolipin have been postulated to bind to NLRP3 and induce its activation., nucleotide-binding and oligomerization domain.
structure
激活剂
NLRP3炎症小体是目前研究最为深人的一种炎症小体, 可被多种病原体及其成分或产物激活,如金黄色葡萄球菌、李斯特菌、白色念珠菌、酿酒酵母菌、仙台病毒、细菌RNA 、尼利亚菌素等;内源性损伤信号或环境致病因子, 如胞外ATP 、尿酸钠晶体、二氧化硅、紫外线等亦可激活NLRP3炎症小体。
Figure2. Signals mediating NLRP3 inflammasome 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