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1、Transcriptome-BasedNetworkAnalysisRevealsaSpectrumModelofHumanMacrophageActivationJiaXue,SusanneV.Schmidt,JilSander,AstridDraffehn,WolfgangKrebs,IngaQuester,DominicDeNardo,TruptiD.Gohel,MartinaEmde,LisaSchmidleithner,HariharasudanGanesan,AndreaNino-Castro.MichaelR.Mallmann,LarisaLabzin,HeidiTheis,
2、MichaelKraut,MarcBeyer,EickeLatz,TomC.Freeman,ThomasUlasandJoachimL.SchultzeClassicmodelofmacrophageactivationIFN-γTLRligands•Expressionofpro-inflammatorycytokines•strongmicrobicidalandtumoricidalactivity•Dampeninflammation•PromotetissueremodellingandtumorIL-4progressionIL-13•Possesimmuneregulator
3、yfunctionsSpectrummodelofmacrophageactivationMacrophagetranscriptomeisdistinctfromotherimmunecellsSchemeforthegenerationandanalysisofactivatedmacrophagesClassicallyactivated(M1)Coregulationanalysis(CRA)……CD14+…TranscriptomeanalysisMacrophages…Alternatively28activationactivated(M2)Self-organizingCo
4、rrelationconditionsmap(SOM)coefficientmatrices(CCM)CRAsupportsspectrummodelformacrophageactivationWithM1andM2WithM1andM2-WithnonM1andM2-stimuliassociatedstimuliassociatedstimuliM2M2M1M1SOMfurthervalidatesspectrummodelformacrophageactivation•foragivenstimulus,genesaregroupedbasedonexpressionlevels•
5、everystimulusischaracterizedbyaspecificclusterstructureCCManalysisreveals10majorclusters-2.780.002.78ClustersSpectrummodelformacrophagepolarizationM1andM2ModelSpectrumModel•Activationstatesrepresentedin3D,withbaselinemacrophages(Mb)atorigin•ExpansionofbinarymodeltoaspectrummodelIdentificationofspe
6、cificgenesassociatedwithdistinctstimuliSOMclusteringIdentificationofgenes29stimuli;enrichedforindividual9498genesstimuliGene:Gene:ZNF77SERINC2Identificationofstimulus-specificgenesets29stimuli;9498genesWGCNAanalysis49modulesME-to-condition•Heatmapofmoduleeigengenetostimulationconditioncorrelationc
7、orrelationGOEnrichmentAnalysisofmodulegenes29stimuli;IFN-γ9498genesWGCNAanalysis49IL-4modulesGOEnrichmentAnalysisGOEnrichmentAnalysisofmodulegenes29stimuli;TPP9498genesWGCNAanalysis49modulesGOEnrichmentAnalysisTr
