Mechanisms of Hematoma Clearance after ICHMechanisms of Hematoma Clearance after ICH脑脑出血后血出血后血肿肿清除机制清除机制IntracerebralHemorrhage(ICH)ICHhasthehighestmortalityrateofallstrokesubtypes.BraininjuryfromICHisinitiallyviamasseffectofthehematoma(primaryinjury)andthenviatoxicbloodcomponentsandpro-inflammatoryandpro-oxidativeprocesses(secondaryinjury).MayoFoundationforMedicalEducationandResearch(mayoclinic.org)PrimaryandSecondaryBrainInjuryMracksoandVeltkamp,2014Hematomaclearanceovertime.(Zhaoetal.,2007)Timecourseofhemoglobincontentinhematoma.(Caoetal,2016)HematomaResolutionMicrogliaandhematomaresolution(Zhaoetal.,2014)Increasednumbersofphagocyticcellswerenoticedintheareaaroundthehematomaasearlyas1-3dafterexperimentalICHThesephagocytesareenlargedandcontainmanyvesicularstructures;henceareactiveintheengulfmentoftoxiccellsPhagocyticmicrogliaandmacrophagesincreaseintheperi-hematomaduringthefirst7dafterICH,thenslowlydecreaseoverthenext2weeks-thisisthesametemporalprofileashematomaresolution;suggestingaroleinthisprocess(E)activatedmicrogliaaroundthehematoma(white arrows at1hourafterICH;(F)themicroglia/macrophages,intheperihematomaarea,at3daysafterICH(Zhaoetal.,2009)EnlargedmicrogliaengulfingRBCs(Zhaoetal.,2014)MicrogliaandMacrophagesMicrogliaarethefirstactivatedinnateimmunecellsintheCNSafteraninjuryandinitiateneuroinflammationthroughthetoll-likereceptors(TLRs)(TaylorandSansing,2013;Linetal.,2012InexperimentalICH,microglialactivationoccursasearlyas1haftercollagenaseinjectionor4hafterbloodinjection(WangandDor,2007;XueandDelBigio,2000).Thispeaksat72handreturnstonormallevels3-4weeksfollowingICH(Wangetal.,2010;Sansingetal.,2011)Blood-derivedmacrophages,inadditiontoresidentmicroglia,aretheprincipalphagocyticcellspresentActivatedmicrogliaaredifficulttodifferentiatefrommacrophagesastheyexpressthesamecellularmarkers(CD11b,Iba-1,isolectinB4)(Ginhouxetal.,2010)MacrophageEngulfingRBChttp:/www.zoology.ubc.ca/berger/B200sample/unit_9_secretion/endocytosis.htmhttp:/ LysosomeLysosomeMacrophageCD36CD163CD91CATALASESODOxidative stressOxidative stressHemeHO-1Fe2+BiliverdinCOHemosiderinHb (AronowskiandZhao,2011)PrimaryandSecondaryBrainInjuryMracksoandVeltkamp,2014Peroxisomeproliferator-activatedreceptor- (PPAR- )andNrf2ICHPPARHpNrf2RBCHemeHx PPARNrf2Nrf2LysosomeLysosomeMacrophageCD36CD163CD91CATALASESODOxidative stressOxidative stressHemeHO-1Fe2+BiliverdinCOHemosiderinHb (AronowskiandZhao,2011)L.ZhaoJ.AronowskiPPAR- -inducedclearanceoferythrocytes(Zhaoetal.,2007)15d-PGJ2,anactivatorofPPAR- ,promotedphagocytosisinprimarymicrogliacultureswithRBCs.RosiglitazonealsoenhancedphagocytosisinthemicrogliaculturesICHHpRBCHemeHx LysosomeLysosomeMacrophageCD36CD163CD91Oxidative stressOxidative stressHemeHO-1Fe2+BiliverdinCOHemosiderinHb Hydrocephalus&NeurologicalDeficitsCSFCirculation&AbsorptionBloodClotsGMHPhagocytosisPPARGW966215d-PGJ2J.FloresJ.ZhangPPAR- TreatmentReducedHydrocephalusandICP28daysafterGerminalMatrixHemorrhageinNeonatalRats(Floresetal,2016)ShamVehicle15d-PGJ2GW9662+15d-PGJ22.5mm1.2mm0.7mm-2.9mmCSF Pressure (mm Hg)PPAR- increasedmicroglialactivation,M2polarization,andtheexpressionofCD36(Floresetal.,2016)NakagawaandChiba,2014Low-densitylipoproteinreceptor-relatedprotein-1(LRP-1)ICHHpRBCHemeHx LysosomeLysosomeMacrophageCD36CD163CD91CATALASESODOxidative stressOxidative stressHemeHO-1Fe2+BiliverdinCOHemosiderinLRP1Hb G.WangJ.TangLRP1&HemopexinincreasedafterICHrLRP-1reduceshematomavolume,BBBdisruptionandbrainedemaafterICH(Wangetal.,2017)ICHHpRBCHemeHx LysosomeLysosomeMacrophageCD36CD163CD91CATALASESODOxidative stressOxidative stressHemeHO-1Fe2+BiliverdinCOHemosiderinLRP1Hb LRP-1reducestheconcomitantoxidativestressandapoptoticcelldeathafterICHLRP-1reducedexpressionofmalondialdehyde,capase3andcleavedcaspase3,andincreasedtheexpressionofSOD1TheseeffectswerereversedwhenLRP-1wasblockedbysiRNA(Wangetal.,2017)Toll-LikeReceptor4(TLR4)ICHHpRBCHemeHx LysosomeLysosomeMacrophageCD36CD163CD91CATALASESODOxidative stressOxidative stressHemeHO-1Fe2+BiliverdinCOHemosiderinHb TLR-4Q.YangInCD36-/-mice,hematomavolumewaslargerandtherateofabsorptionslowerthaninwildtypemicePhagocytosisofRBCswasreducedsignificantlyinCD36-/-micecomparedtowildtypeInhibitionofCD36withananti-CD36AntibodyalsodecreasedtheabilityofmicrogliatophagocytoseRBCsKnockoutofTLR-4andMyd88resultedinsignificantlyincreasedCD36expressionandmicrogliaphagocyticactivityTLR-4 signaling may downregulate CD36 expression and hematoma absorptionTLR-4andCD36SignalinginHematomaResolution(Fangetal.,2014)CD36MediatedHematomaAbsorption(Fangetal.,2014)ICHpatientswithCD36deficiencyhadlargerhematomavolumescomparedtopatientswithnormalCD36expressionat7dafterICHonsetThehematomaabsorptionratewaslowerinCD36-normalICHpatientsthanthosewhoweredeficientTheNIHSSscoresweresignificantlyhigherinICHpatientswithCD36deficiencythanthosewithoutat14and30days;mRSscoresat90dwerealsosignificantlyhigherinCD36-deficientpatientsCD36 plays an important role in promoting hematoma absorption in ICH patientsICHHpRBCHemeHx LysosomeLysosomeMacrophageCD3