LPS TLR4 信号通路

LPSTLR4SignalTransductionPathwayIntroduction1.Sepsis(败血症)isalife-threateningconditioninwhichbacterialinfectionoccursinthebloodstreamofanindividual.Thisconditionisalsoreferredtoassystemicinflammatoryresponsesyndrome(SIRS-全身性炎症反应综合征).Introduction2.Systemicinflammatoryresponsesyndrome(SIRS全身性炎症反应综合征)leadstoMultipleorgandysfunctionsyndrome(MODS多器官功能障碍综合征).Introduction3.Sepsiscanbecausedduetointernalorexternalinfections.Oncethemicroorganismsenterthehumanbody,theyhavethepotentialtospreadtootherpartsofthebodyviabloodcirculationIntroduction4.Itiscommonlythatbacterialendotoxinsuchaslipopolysaccharide(LPS)causessepsis.TherealmechanismofsepsisliesintheToll-likereceptorsthatsuppresssepsiscausedbytissueinjuryorendotoxin.WhenToll-likereceptors'initialsuppressionroleisoverwhelmed,sepsisensues.LPSTLR4pathway1.TLRPathwayisanancientinnateimmunesystemTollpathwaysinDrosophilaandmammalsLPSTLR4pathway2.AnintroductionofLPS2.1Asacomponentofthegramnegativecellenvelope,Itcomprisesthreeparts:1).Oantigen(orOpolysaccharide)2).Coreoligosaccharide3).LipidA2.2ThelipidAdomainisresponsibleformuchofthetoxicityofGram-negativebacteria.LPSTLR4pathway3.PAMPsPathogenassociatedmolecularpatterns(LPS)PAMPsaremoleculesassociatedwithgroupsofpathogens,thatarerecognizedbycellsoftheinnateimmunesystem.Thesemoleculescanbereferredtoassmallmolecularmotifsconservedwithinaclassofmicrobes;thereforemicrobe-associatedmolecularpattern,MAMPLPSTLR4pathway4.PRRsPatternrecognitionreceptors,areproteinsexpressedbycellsoftheinnateimmunesystemtoidentifyPAMPs.3.2ThelipidAdomainisresponsibleformuchofthetoxicityofGram-negativebacteria.TollLikeReceptorsLPSTLR4pathway5.GeneralizedmajorsignaltransductionpathwayofTLR4LPSTLR4pathway6.TLR4pathwayInitiationLPSstimulationofmammaliancellsoccursthroughaseriesofinteractionswithseveralproteinsincludingtheLPSbindingprotein(LBP),CD14,MD-2andTLR4.LBPisasolubleshuttleproteinwhichdirectlybindstoLPSandfacilitatestheassociationbetweenLPSandCD14.CD14isaglycosylphosphatidylinositol-anchoredprotein,whichalsoexistsinasolubleform.CD14facilitatesthetransferofLPStotheTLR4/MD-2receptorcomplexandmodulatesLPSrecognition.MD-2isasolubleproteinthatnon-covalentlyassociateswithTLR4butcandirectlyformacomplexwithLPSintheabsenceTLR4.AlthoughnoevidencesuggeststhatTLR4canbindLPSdirectly,TLR4canenhancethebindingofLPStoMD-2[26].ThereforeLPSstimulationofTLR4,includestheparticipationofseveralmolecules,andthecurrentlyfavouredmodelisoutlined.LPSTLR4pathway7.TLR4adaptorsUponLPSrecognition,TLR4undergoesoligomerizationandrecruitsitsdownstreamadaptorsthroughinteractionswiththeTIR(Toll-interleukin-1receptor)domains.7.1TheMyD88-dependentpathwaytoberesponsibleforproinflammatorycytokineexpression,7.2TheMyD88-independentpathwaymediatestheinductionofTypeIinterferonsandinterferon-induciblegeneLPSTLR4pathway8.MyD88-dependentpathwayMyD88deathdomainrecruitsIRAK-4IRAK-4recruits,activatesanddepredatesIRAK-1TRAF6formsacomplexwithUBC13(ubiquitin-conjugatingenzyme13)andUEV1A(ubiquitin-conjugatingenzymeE2variant1isoformA),andactivatesTAK1(transforminggrowthfactor-β-activatedkinase1).TAK1thenactivatesdownstreamIKK(IκBkinase)andMAPKpathways.IKKα,IKKβandIKKγformacomplexandphosphorylateIκBproteins.ThendegradationofIκBproteinsandthesubsequenttranslocationofthetranscriptionfactorNF-κB,whichcontrolstheexpressionofproinflammatorycytokines,inadditiontootherimmunerelatedgenes.LPSTLR4pathway9.MyD88-independentpathwayTRIFplaysakeyroletheactivationoftranscriptionfactorIRF3,thelate-phaseactivationofNF-κBandMAPK.thedeletionofbothMyD88andTRIFleadstoseverelyimpairedNF-κBandMAPKactivation.theinductionofTypeIinterferonswasdefectiveinTRAF3-deficientcells.IRF3,togetherwithNF-κB,activatesthetranscriptionoftargetgenes,suchasTypeIinterferons.LPSTLR4pathway10.NegativeregulationofTLR4signalingpathwayRP105ST2LTRIAD3ASOCS-1IRAK-MA20Thankyouforyourattention!