動脈粥樣硬化研究進(jìn)展——ByYahooM.D.Dependentonligationofso-calledpatternrecognitionreceptors(PRR)TwomajorclassesofPRRs:endocytosolicscavengerreceptors(SR)thefamilyoftoll-likereceptors(TLR)InnateimmunityNecessaryforpathogenuptakeandantigenpresentation,oxidizedlipidsarerecognizedandabsorbedviascavengerreceptorsonactivatedmacrophagesthatrecognizeoxLDLincludeSRA-1,SRA-2,MARCO,CD36,SR-B1,LOX-1andPSOXApossibleatheroprotectivemechanismofSRmightbetheorchestrationofcholesteroleffluxfromthelesionSROnceactivated,induceastronginflammatoryresponseTLR-1,2,4and6aspotentialpro-atherogenicmediators,whileTLR-3andTLR-7mightexhibitathero-protectiveeffectsDeletionofMyD88,animportantadaptorproteinformostTLRsresultedinthelargestreductionofatheroscleroticplaquesTLRPotentialantigensactivatingTLRswithintheplaqueincludetheendogenousstressmoleculeheatshockprotein60(HSP60)andox-LDLactivatesthenuclearfactorκB(NF-κB)andthemitogen-activatedproteinkinase(MAPK)pathways,triggeringtheproductionofpro-inflammatorycytokinesliketumornecrosisfactor-α(TNF-α)andIL-1βaswellasmatrixmetalloproteinases.Veryrecently,theinflammasome(炎性體),amacromolecularaggregationofintracellularPRRsthatinducesIL-1βproductioninmacrophagesviacaspase-1,wasimplicated

inatherogenesischolesterolcrystalsactivatetheinflammasomeNLRP3therebytriggeringIL-1βproductiontargetingtheinterplayofcholesterolcrystalsandtheinflammasomeInvolvedinremovalofdebrisandapoptoticcellsAlternativepathway(旁路途徑):triggeringtheformationoftheanaphylatoxinsC3aandC5aandtheterminalcomplementcomplex(TCC)exhibitspro-atherogeniceffectsClassicalandthelectinpathway(經(jīng)典和凝集素途徑)hasanti-atheroscleroticeffectsbyfacilitatingdebrisremovalThecomplementsystemWashardlydetectableinstableplaqueswhileinunstablelesionsitco-localizedwithMMP-1andMMP-9situatedaroundcholesterolcleftsabletoinduceproinflammatorycytokinesaswellasMMP-1andMMP-9productioninplaquemacrophagesC5aandC3bamuchhigherC3bconcentrationinrupturedplaqueswhencomparedtostableplaquesAllabovesuggestanimportantroleofC3aandC5ainmatrixdegradationleadingtoplaquerupturebothtreatmentwithanti-C5a-antibodiesanddirectblockingoftheC5a-receptorattenuatedatherosclerosisextentandinducedamorestableplaquephenotypeinanimalmodelsInpatients,plasmalevelsofC3a,C5aandtheTCCwerepredictiveofcardiovasculareventsindifferentpatientcohorts.Furthermore,serumlevelsofC5apredictedrestenosisafterfemoralballoonangioplastyandC3aandC5awerepredictiveoflatelumenlossaftertreatmentwithdrugelutingstentsinstableCADpatients.CD16-positivemonocyteswereconsideredtobeapro-inflammatorysubsetofmonocytesincreasedproductionofinflammatorycytokinessuchasTNF-αMonocyteandmacrophageheterogeneity“classicalmonocytes”(CM;CD14++CD16-),“intermediatemonocytes”(IM;CD14++CD16+)“non-classicalmonocytes”(NCM;CD14+CD16++).Inadiposepatients,thepercentageofNCMwasstronglyincreasedandcorrelatedwithfatmassandfastingglucosetheNCM-proportiondecreasedtogetherwithpatient’sweightandintima-mediathicknessThecorrelationbetweenBMIandNCM,negativecorrelationbetweenNCMandHDL-cholesteroltheproportionofCD16+monocytescorrelatedwithintima-mediathicknessCD16+cellswerecorrelatedwithplaqueinstabilityandwereinverselycorrelatedwithplaquestabilizationSimilartomonocytes,alsomacrophagesexhibitheterogeneityandplasticityTreatmentwithIFN-γandLPSskewsmacrophagestotheM1phenotypecharacterizedbyincreasedsecretionofpro-inflammatorycytokines,ROS,tissuefactorandmetalloproteinasesMacrophagesM2macrophagesdefinedbyahighexpressionofCD206,IL-10andarginase-1ariseviainvitrostimulationwithIL-4,IL-10orIL-13andexhibitanti-inflammatoryandtissueregeneratingeffectsUnderphysiologicconditionscomprisesinspectionandinductionandmaintenanceofperipheraltoleranceofT-cellsagainstautoantigensTwosubtypesofDCscanbefoundintheevolvingatheroscleroticplaque,the?conventionalmyeloid（髓系）

DCs(mDCs)

?plasmacytoidDCs(pDCs)DendriticcellsDifferintheirexpressionprofileofPRRsmDCsexpressprimarilyTLR-4sensingbacteriabutalsoautoantigenssuchasoxLDLandHSP-60pDCspredominantlyexpressTLR-7,TLR-8andTLR-9，Onceactivated,pDCsproduceincreasedamountsofIFN-γmodulatingDCactivitymightalsorepresentaninterestingtargetcirculatingantibodiesagainstoxidation-specificepitopes(OSE)onoxLDLandthedetectionofT-cellswithinatheroscleroticplaqueswerefirsthintsontheinvolvementofadaptiveimmuneresponsesinatherosclerosisAdaptiveimmunityActaspro-atherogeniccells,astheyproduceincreasedlevelsofIFN-γ,IL-12andIL-18,accelerateatherogenesisTh-1cellsconflictingdataexistsfortheroleIL-4wereshowntoexhibitbothpro-andantiatheroscleroticeffectsIL-13wasshowntoattenuateatherosclerosisTh2-cellstheroleofIL-17-producingTh-cells,theTh17-cells,isunclear,asbothpro-atherosclerotic,neutralandanti-theroscleroticeffectswereshownTregs

wereshowntoexhibitatheroprotectiveeffects:producetheanti-inflammatorycytokinesIL-10andtransforminggrowthfactor-γ(TGF-γ),Th17-cellsandTregsRecently,aT-cellreceptorreactivetoApoB100wasidentifiedandcloned,demonstratingforthefirsttimethatnaturallyoccurringautoimmunityagainstLDLdoesexist.TheexistenceofLDL-specificT-cellreceptorsfurthermoreimpliestheexistenceofLDL-specificTregs,probablyresponsibleforperipheraltoleranceagainstLDL.ImmunomodulationwithApoB100immunizationmightrepresentaninterestingandpromisingtherapeuticapproachClinicalpractice:Oneinterestingtargetmightbemalondialdehyde-(MDA,丙二醛)-modifiedApoB100p45peptide,asimmunizationwiththispeptidetriggeredthegenerationofreactiveantibodiesoftheIgGclass.Inducingox-LDLremovalandinterferingwithpro-inflammatoryeffectsagainstox-LDLinparticularleukocytessuchasmonocytesandneutrophils,activelyparticipatesinthrombusformationatmanystagesDuringarterialthrombosis,activatedplateletsofthegrowingclotreleasechemokinesandexpressadhesionmoleculessuchasP-selectin,causingsubsequentrecruitmentofmonocytesandneutrophilsintothegrowingthrombusImpactofthecoagulationsystemActivatedplateletsformaggregateswithmonocytesthatexpresstheligandforP-selectin,namelyP-selectinglycoproteinligand-1(PSGL-1).Thesemonocyte-plateletaggregates(MPA)wereshowntobeelevatedinpatientswithunstableangina,acutemyocardialinfarctionandaftercoronaryinterventioninstablepatientsTheclassicalnotionofTFasameresubendothelialproteinhasbeenchallengedbythedetectionofTF-expressingmonocyteswithinthebloodstreamIntra-vascularTFandTFwithinatheroscleroticplaquesmayrepresentthemaintriggerofatherothrombosisfollowingplaqueruptureTFExhibitspro-inflammatoryeffectsbyactivatingPAR-receptorsthatareexpressedbycellsthroughouttheatheroscleroticlesionDirectthrombininhibitionwithmelagatrananddabigatranreducedplaqueformation,promotedplaquestabilityandimprovedendothelialfunctioninApoE-/-miceThrombinadiposetissueisamajorendocrineandparacrineorganproducingnumerousenzymes,hormonesandgrowthfactorswhicharecollectivelytermedasadipokinese.g.adiponectin,leptin,resistin,tumornecrosisfactor-alpha(TNF-a),interleukin-6(IL-6),plasminogenactivatorinhibitor-1(PAI-1),atrialnatriureticpeptideandangiotensinogenAdipokinesModulateinsulinsensitivity,glucose/fatmetabolismandobesitySeveraldirectactionsofadipokinesonendothelialfunction,vascularhomeostasisandatherogenesiswhichareindependentoftheireffectsonglucoseandfatmetabolismLeptinamoderateassociationbetweenleptinandtheriskforcoronaryarterydisease,whichwasmainlydependentonbodymassindexaneuroprotectiveroleofleptinagainstischemicneuronalinjurymediatedbyERK1/2activationPPAR-γactivatorslikethiazolidinediones,downregulateleptingeneexpressionandthereforeinhibitleptin-directedmigrationofvascularsmoothmusclecellthroughinhibitionofAktandeNOSpromotetheatheroscleroticprocessbyupregulatingtheexpressionofVCAM-1,E-selectinICAM-1Troglitazone,aPPAR-γactivator,wasshowntodownregulateTNF-αexpressioninadipocytesandreducestheTNF-amediatedendothelialexpressionofVCAM-1andICAM-1TNF-αincreaseET-1levelswithoutalteringNOproductionEndothelialdysfunctionmediatedbyreducedeNOSexpressionandNOproductionviaoxidativestressandactivationofp38andc-JunNH2-terminalmitogen-activatedproteinkin