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1、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1.引言2.NLRP3炎性小体3.NLRP3与IBD4.总结1.引言IBDPAMPs/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(familialcoldutoinfl
2、ammatorysyndrome,FCAS)、穆-韦综合征(Muckle-Wellssyndrome,MWS)和新生儿期多系统炎症综合征(neonatalonsetultisysteminflammatorydisease,NOMID),上述疾病统称为隐热蛋白-相关周期综合征(cryopyrinassociatedperiodicsyndrome,CAPS)。NLRsN-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/N
3、LRB/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)2.NLRP3InflamasomedistributionStructureMechanismsofitsactivationSignal1:PrimingSignal2:ActivationInhibitionfunction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。Figure1.Sc
4、hematicofNLRP1,NLRP3,NLRC4,andAIM2inflammasomes.HumanNLRP1caninteractwithASCandcaspase-1viaanN-terminalPYDandalsobindcaspase-5tothecomplexviatheC-terminalCARD.Muramyldipeptide(MDP),Bacillusanthracislethaltoxin,andToxoplasmagondiicaninducetheactivationoftheNLRP1inflammasome
5、.MouseNlrp1bdoesnotpossessafunctionalN-terminalPYD,hencecaspase-1mayinteractwithitsC-terminalCARD.NLRP3interactswithASCthroughanN-terminalPYDdomain,whichthenrecruitscaspase-1.MitochondrialDNA(mtDNA)andcardiolipinhavebeenpostulatedtobindtoNLRP3andinduceitsactivation.,nucleo
6、tide-bindingandoligomerizationdomain.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.SignalsmediatingNLRP3inflammasomepriming.Uponengagement,patternrecognitionrece
7、ptors(PRR),suchasTLR4andNOD2,orcytokinereceptors,suchasTNFRandIL-1R,activateNF-B,leadingtothetranscriptionandtranslationofNLRP3andpro-IL-1.DissociationofHSP90andSGT1fromNLRP3isrequiredforNLRP3inflammasomeactivation.Additionally,NLRP3undergoesdeubiquitylationbytheJAMMdomain
8、–containingZn2+metalloproteasedeubiquitinatingenzymeBRCC3,whichiscrucialforsubsequentNLRP