NLRP炎性小體與炎癥性腸病

1.引言2.NLRP3炎性小體3.NLRP3與IBD

4.總結(jié)1.引言IBDPAMPs/DAMPs與PRRs(TLRs/NLRs)NF-κB通路炎性小體(*NLRs/ASC/Caspase/AIM2)NLRP3炎性小體的活化可致無(wú)活性的caspase-1前體轉(zhuǎn)化為活性caspase-1，后者可裂解白細(xì)胞介素（IL-1β）、IL-18、IL-33前體以形成活性形式并分泌。NLRP3已證實(shí)與人類多種自身免疫病相關(guān)，如家族性寒冷自身炎癥綜合征（familialcoldutoinflammatorysyndrome,FCAS）、穆-韋綜合征（Muckle-Wellssyndrome，MWS）和新生兒期多系統(tǒng)炎癥綜合征（neonatalonsetultisysteminflammatorydisease,NOMID），上述疾病統(tǒng)稱為隱熱蛋白-相關(guān)周期綜合征（cryopyrinassociatedperiodicsyndrome,CAPS）。NLRsN-terminal效應(yīng)區(qū)

含有一個(gè)熱蛋白結(jié)構(gòu)域(PYD),caspase招募結(jié)構(gòu)域(CARD),或一個(gè)桿狀病毒凋亡抑制重復(fù)結(jié)構(gòu)域(BIR),NLRs亞類的分類依據(jù)（NLRA/NLRB/NLRC/NLRP/NLRX）。Central

核苷酸結(jié)合寡聚化結(jié)構(gòu)域(NACHT），是各種NLRs的共同特征。C-terminus亮氨酸重復(fù)區(qū)(LRR)2.NLRP3InflamasomedistributionStructureMechanismsofitsactivationSignal1:PrimingSignal2:ActivationInhibitionfunction

分布NLRP3在中性粒細(xì)胞、單核細(xì)胞、淋巴細(xì)胞、樹(shù)突細(xì)胞、成骨細(xì)胞、上皮細(xì)胞（口咽部、食管、外宮頸、尿道）、皮膚角質(zhì)形成細(xì)胞等均有表達(dá)。Figure1.SchematicofNLRP1,NLRP3,NLRC4,andAIM2inflammasomes.HumanNLRP1caninteractwithASCandcaspase-1viaanN-terminalPYDandalsobindcaspase-5tothecomplexviatheC-terminalCARD.Muramyldipeptide(MDP),Bacillusanthracislethaltoxin,andToxoplasmagondiicaninducetheactivationoftheNLRP1inflammasome.MouseNlrp1bdoesnotpossessafunctionalN-terminalPYD,hencecaspase-1mayinteractwithitsC-terminalCARD.NLRP3interactswithASCthroughanN-terminalPYDdomain,whichthenrecruitscaspase-1.MitochondrialDNA(mtDNA)andcardiolipinhavebeenpostulatedtobindtoNLRP3andinduceitsactivation.,nucleotide-bindingandoligomerizationdomain.structure激活劑NLRP3炎癥小體是目前研究最為深人的一種炎癥小體,可被多種病原體及其成分或產(chǎn)物激活,如金黃色葡萄球菌、李斯特菌、白色念珠菌、釀酒酵母菌、仙臺(tái)病毒、細(xì)菌RNA、尼利亞菌素等;內(nèi)源性損傷信號(hào)或環(huán)境致病因子,如胞外ATP、尿酸鈉晶體、二氧化硅、紫外線等亦可激活NLRP3炎癥小體。Figure2.SignalsmediatingNLRP3inflammasomepriming.Uponengagement,patternrecognitionreceptors(PRR),suchasTLR4andNOD2,orcytokinereceptors,suchasTNFRandIL-1R,activateNF-B,leadingtothetranscriptionandtranslationofNLRP3andpro-IL-1.DissociationofHSP90andSGT1fromNLRP3isrequiredforNLRP3inflammasomeactivation.Additionally,NLRP3undergoesdeubiquitylationbytheJAMMdomain–containingZn2+metalloproteasedeubiquitinatingenzymeBRCC3,whichiscrucialforsubsequentNLRP3inflammasomeactivation.UponactivationoftheNLRP3inflammasome,activecaspase-1canprocesspro-IL-1andpro-IL-18intotheirmaturesecretedforms.Signal1:primingFigure3.InhibitionofNLRP3inflammasomeactivation.TypeIIFNsactingthroughIFNARinhibitthetranscriptionofpro-IL-1throughtheupregulationoftheanti-inflammatorycytokineIL-10.TypeIIFNsandIFN-inhibitNLRP3throughtheproductionofnitricoxide(NO)viatheinduciblenitricoxidesynthase(iNOS),resultinginnitrosylationofNLRP3.InteractionofmatureormemoryTcellswithmacrophagesviaCD40–CD40LresultsininhibitionoftheNLRP3inflammasome.ElevationofcellularcAMPlevelsalsoresultsintheinhibitionofNLRP3.ThemicroRNAmiR-223regulatestheamountofNLRP3mRNAand,consequently,NLRP3expression.inhibitionSignal2:activationFigure4.RegulationofNLRP3inflammasomeactivationinresponsetoionfluxesandmitochondrialdysfunction.K+effluxisrequiredforNLRP3inflammasomeactivationandisachievedeitherdirectlybybacterialpore-formingtoxins,suchasnigericin,orindirectlyviareceptorssuchasthepurinergicreceptorforATP,P2X7R.Duringtheregulatoryvolumedecreaseresponsetocellswelling,Ca2+fluxescanberegulatedbythetransientreceptorpotentialreceptorsTRPM7andTRPV2.Ca2+influxcanalsobemediatedviatheROS-sensitiveTRPM2.可能的激活機(jī)制ATP-依賴的鉀離子外流線粒體功能障礙ROS溶酶體破裂核糖體功能障礙3.NLRP3炎性小體與IBD(1)CD遺傳易感性2001年，McGovern等發(fā)現(xiàn)了CD的第一個(gè)易感基因NOD2/CARD15，因NLRP3和NOD2蛋白同屬NLR家族成員，由此提示NLRP3亦可能與CD相關(guān)。對(duì)瑞典人的研究發(fā)現(xiàn)NLRP3炎癥小體組分NLRP3、CARDS8基因多態(tài)性與NOD2等位基因?yàn)橐吧偷哪行缘腃D易感性相關(guān);對(duì)加拿大歐洲后裔的研究發(fā)現(xiàn)位于NLRP3基因下游調(diào)控區(qū)的一組SNPs與CD易感性相關(guān),但該相關(guān)性未能在英聯(lián)邦人群中被復(fù)制,表明此種相關(guān)性受地域和遺傳背景的影響。(2)IBD小鼠的相關(guān)研究今年有研究發(fā)現(xiàn)NLRP3炎癥小體組分缺陷(NLRP3-/-或ASC-/-或Caspase-1-/-)小鼠對(duì)葡聚糖硫酸鈉(DSS)或三硝基苯磺酸（TNBS）誘導(dǎo)的結(jié)腸炎更為易感。給予重組IL-18可使caspase-1缺陷小鼠的重量減輕明顯緩解,表明NLRP3炎癥小體通過(guò)IL-18對(duì)實(shí)驗(yàn)性結(jié)腸炎發(fā)揮保護(hù)作用,發(fā)揮作用的主要是腸上皮細(xì)胞中的NLRP3炎癥小體。然而亦有研究發(fā)現(xiàn)NLRP3-/-小鼠對(duì)DS誘導(dǎo)的結(jié)腸炎耐受,其機(jī)制可能與結(jié)腸促炎細(xì)胞因子IL-1β、IL-18、腫瘤壞死因子-α(TNF-α)等產(chǎn)生減少有關(guān)。實(shí)驗(yàn)結(jié)果的不一致性可能是由實(shí)驗(yàn)小鼠的遺傳背景，腸道菌群組成以及實(shí)驗(yàn)干預(yù)方案不同所引起。(3)材料與方法Wild-typemiceandmicedeficientinNLRP3,ASC,caspase1,interleukin-1(IL-1),IL-1receptortypeI(IL-1RI),IL-18R,myeloiddifferentiationfactor88(MyD88),or5-LOXwereused.neutrophilinflux,LTB4activity,cytokine(IL-1,CXCL1)production(byenzyme-linkedimmunosorbentassay),synovialmicrovasculaturecelladhesion(byintravitalmicroscopy).Cleavedcaspase1andproductionofreactiveoxygenspecies(ROS)wereanalyzedinmacrophagesbyWesternblottingandfluorometricassay,respectively.4.總結(jié)雖然對(duì)NLRP3炎性小體的研究非常廣泛，但不夠深入。炎性小體組裝的激活信號(hào)通路還不清楚，如細(xì)胞鉀離子外流如何激活炎性體，線粒體如何發(fā)揮作用。目前，NLRP3炎性體與腸道炎癥的研究很少，炎性體信號(hào)通路參與包括IBD在內(nèi)的一些炎癥性疾病，可作為治療IBD的藥物靶點(diǎn)，對(duì)其研究有助于發(fā)現(xiàn)新型的治療藥物。參考文獻(xiàn)1.AllenIC,TeKippeM,WoodfordRM,etal.TheNLRP3inflamasomefuntionsasanegativer