JaneLattin,*DavidA.Zidar,†KateSchroder,*StuartKellie,*,‡DavidA.Hume,*,§andMatthewJ.Sweet*,‡,1*CooperativeResearchCentreforChronicInflammatoryDiseasesand§SpecialResearchCentreforFunctionalandAppliedGenomics,InstituteforMolecularBioscience,and‡SchoolofMolecularandMicrobialSciences,UniversityofQueensland,Brisbane,Queensland,Australia;and†DivisionofCardiology,DukeUniversityMedicalCenter,Durham,NorthCarolina,USA
Abstract:G-protein-coupledreceptors(GPCRs)arewidelytargetedindrugdiscovery.Asmacro-phagesarekeycellularmediatorsofacuteandchronicinflammation,wereviewheretheroleofGPCRsinregulatingmacrophagefunction,withafocusoncontributiontodiseasepathologyandpo-tentialtherapeuticapplications.Withinthisanaly-sis,wehighlightnovelGPCRswithamacrophage-restrictedexpressionprofile,whichprovideave-nuesforfurtherexploration.Wealsoreviewanemergingliterature,whichdocumentsnovelrolesforGPCRsignalingcomponentsinGPCR-indepen-dentsignalinginmacrophages.Inparticular,weexaminethecrosstalkbetweenGPCRandTLRsignalingpathwaysandhighlightGPCRsignalingmoleculeswhicharelikelytohaveuncharacterizedfunctionsinthiscelllineage.J.Leukoc.Biol.82:16–32;2007.
KeytorWords:-arrestin⅐heterotrimeric⅐immune⅐Toll-likerecep-⅐kinase⅐inflammation
INTRODUCTION
G-protein-coupledreceptor(GPCR)classification
Theseven-transmembranedomainGPCRsconstitutethelarg-estknownsuperfamilyofcell-surfacereceptors.Theycontrolavarietyofcellularandphysiologicalprocesses,suchasper-ceptionoflight,pain,tasteandsmell,neurotransmission,digestion,andcardiovascularregulation.GPCRsarealsoim-portantregulatorsofinnateandacquiredimmunity.Thehu-mangenomeencodesϳ1000distinctGPCRs,whichareclas-sifiedintothreemainfamiliesandnumeroussubfamiliesonthebasisofsequencesimilarity.
Therhodopsin-likefamily(orFamilyA)isbyfarthelargestofthesefamiliesandconsistsofrhodopsin,adenosine,mela-nocortin,neuropeptide,olfactory,chemokine,andmelatoninreceptors,amongstothers.Thesecretin-likefamily(orFamilyB)consistsofϳ25members,includingthereceptorsforthegastrointestinalpeptidehormonefamily(secretin,glucagon,vasoactiveintestinalpeptide,andgrowthhormone-releasinghormone),calcitonin,andparathyroidhormone,aswellascorticotrophin-releasinghormonereceptors.Themetabotropic
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receptorfamily(orFamilyC)isthesmallestfamilyandcon-sistsoftheGABABreceptor,thecalcium-sensingreceptor,andsometastereceptors[1–3].Recently,MetpallyandSowdhamini[4]usedphylogeneticclusteringacrossspeciesasanalternativeapproachtoclassifyGPCRs.Thisstudyidenti-fiedeightmajorgroupsofGPCRsinhumans:peptiderecep-tors,chemokinereceptors,nucleotideandlipidreceptors,bio-genicaminereceptors,secretinreceptors,glutamatereceptors,celladhesionreceptors,andfrizzledreceptors.Theseweredividedfurtherintoatotalof32clusters.Despitethisapparentdiversity,allGPCRsmediatetheireffects,atleastinpart,throughcouplingtoheterotrimericG-proteinsuponagonist-inducedactivationofthereceptor.
OverviewofGPCRsignaling
Figure1outlinesthecentralroleofheterotrimericG-proteinsinGPCRsignaling.Intheabsenceofagonist,the␥-subunitassociateswiththeGDP-bound␣-subunit.AgonistoccupationofGPCRsstimulatesthereleaseofthe␣-subunitfromthe␥-subunit,andthefreesubunitsthenpositivelyornegativelyregulateeffectorenzymes,suchasionchannels,adenylylcyclases,andPLs.Theregulationofthesesecondmessengersmodulateslevelsofintracellularmediators,suchascAMP,intracellularcalcium,phosphoinositides,andDAG,whichinturnactivateorinhibiteffectorssuchasPKA,PKC,andPI-3K,ultimatelyleadingtoabiologicalresponse(Fig.1,Steps1and2)[5–7].Anarrayofdifferent␣-,-,and␥-subunitshasdiverseeffectsoneffectorsystemsandthusenablestheacti-vationofdistinctsignalingpathwaysandbiologicalresponses.Thisprocessisnotreviewedindetailhere,andinstead,thereaderisreferredtoextensivereviewsabouttherolesofdifferentheterotrimericG-proteincomplexesinGPCRsignal-ing[3,8].
Uponagonistactivationofreceptors,arapidattenuationofreceptorresponsivenessoccursthroughfeedbackmechanisms,whichpreventacuteandchronicoverstimulationoftherecep-tor(Fig.1).Thisprocessofdesensitizationiscontrolledby
1Correspondence:InstituteforMolecularBioscience,UniversityofQueens-land,St.Lucia,Brisbane,QLD4072,Australia.E-mail:m.sweet@imb.uq.edu.au
ReceivedJanuary22,2007;revisedMarch29,2007;acceptedApril1,2007.
doi:10.1189/jlb.0107051
0741-5400/07/0082-0016©SocietyforLeukocyteBiology
.
Fig.1.GPCRsignaling.1.AgonistoccupationofGPCRsstimulatesachangeinconformationofthereceptor,whichcouplesthereceptortotheG-proteinandpromotestheexchangeofGDPforGTPonthe␣-subunit.2.TheGTP-bound␣-subunitdissociatesfromthe␥-subunit;thefreesubunitsthenregulateeffectorenzymespositivelyornegatively,ultimatelyleadingtoabiologicalresponse.3.G-proteinsignalingisterminatedviareceptordesensitizationandinternalization.Desensitizationisinitiatedbyphosphorylationofactivatedreceptorswithinthethirdintracellularlooporcarboxy-terminaltailbyGPCRkinases(GRKs)and/orsecondmessenger-dependentproteinkinases.4.Thisphosphorylationpromotestranslocationofthecytosolicarrestinproteinstothemembrane,wheretheybindtothereceptorandpromoteinternalization.InthecaseofClassAreceptors,-arrestins(ARRBs)dissociatefromthereceptorpriortointernalization,andtheyremainassociatedwithClassBreceptorsthroughoutreceptorinternalization.5.InternalizedreceptorsmaypromoteasecondroundofsignalingthroughtheabilityofARRBstoactasscaffoldsintheassemblyofsignalingcomplexes.6.Thereceptoristhenrecycledtothemembranetoundergofurtherroundsofsignalingoristargetedfordegradation.ExamplesofGPCRsorcomponentsoftheGPCRsignalingmachinerywhicharehighlyexpressedorregulatedinmacrophagesarehighlightedinredboxes(refs.[27,29,39–41,85,88,170–172,185,221,222];J.LattinandM.J.Sweet,unpublisheddata;http://symatlas.gnf.org/SymAtlas/).ET-A/B,Endothelin-A/B;EMR1,epidermalgrowthfactor(EGF)module-containingmucin-likehormonereceptor;FPR,formylpeptidereceptor;PLC-,phospholipaseC-;ASK,apoptosissignal-regulatingkinase1;MKK4,MAPKkinase4;MEK,MKK;DAG,diacylglycerol;PKC,proteinkinaseC;RhoGEFs,Rhoguaninenucleotideexchangefactors.
threefamiliesofregulatorymolecules:secondmessenger-de-pendentproteinkinases,GRKs,andarrestins[9–11].Apartfromreceptordesensitizationandinternalization,thesefami-liesalsoregulateGPCRtrafficking,receptorrecycling,anddownstreamsignaling.
DesensitizationisinitiatedbyphosphorylationofactivatedGPCRswithinthethirdintracellularlooporthecarboxyl-terminaltailbyGRKsand/orsecondmessenger-dependentproteinkinases[12–14].Thisphosphorylationpromotestrans-locationofthecytosolicadaptorarrestinproteinstothemem-brane,wheretheybindtothereceptorandpromoteinternal-izationthroughinteractionwith2-adaptinandclathrincom-ponentsoftheendocyticmachinery[15–17].Asreceptor-containingendosomesmature,thedecreasingpHresultsindissociationoftheligandfromitsreceptorandreceptorde-phosphorylation.Thereceptoristhenrecycledtothemem-branetoundergofurtherroundsofsignaling(resensitization)oristargetedfordegradationtofurtherdown-regulatesignaling(Fig.1).GPCRscanbedividedintotwoclasses,ClassAorB,accordingtotheiraffinityforthe-arrestin(ARRB).ClassAreceptorsbindARRB2withmuchhigheraffinitythanARRB1,andClassBreceptorsbindbothARRBswithequalaffinities.TheclassesaredistinguishedfurtheronthebasisoftheirassociationwithARRBduringreceptorinternalization;ARRBsdissociatefromClassAreceptorspriortointernaliza-tion,andARRBsremainassociatedwithClassBreceptorsthroughoutreceptorinternalization(Fig.1).ClassAreceptorsrecyclerapidly,returningtothecellsurfacewithinϳ30minofinitialstimulation,andClassBreceptorsremainARRB-andendosome-associated1hafteractivation[18,19].Theprocess
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ofreceptordesensitizationandresensitizationisreviewedex-tensivelyelsewhere[20,21].
GPCRFUNCTIONINMACROPHAGES
Macrophagesareimportantcellularmediatorsofacuteandchronicinflammation.HostcytokinessuchasIFN-␥andbac-terialproducts,suchastheTLR4agonistLPS,elicittheproductionofproinflammatorymediatorsfrommacrophages.RegulationofmacrophagefunctionbyTLRagonistshasbeenacentralfocusofresearchininnateimmunityoverthelast10yearsandhasbeenreviewedextensively[22,23].Itisimpor-tanttonotethathost-andpathogen-derivedGPCRagonistsalsoregulatetheinflammatoryresponsethroughmodulatingmacrophagechemotaxis,survival,andactivation(forthepur-posesofthisreview,wedefinemacrophageactivationasaninduciblechangeinfunction,forexample,analteredproduc-tionofinflammatorymediators).Thechemokinereceptors,whichcomprisealargebranchoftherhodopsin-likefamily,modulatethenumbersofcellsininflammatorysitesbyleuko-cyteadhesionandmigration.Inmanycases,theyalsocontroltheactivationstateoftherecruitedcells.Consequently,thisfamilyhasbeenreviewedextensively[24–26].Forthisreason,wewillfocusonotherGPCRsthatarelesswell-studiedinmacrophagebiologyorwerenotincludedinrecentreviews,andconsidertheirfunctionininflammation.Figure2providesanoverviewofsomeofthemajorfunctionsofGPCRsinmacrophages.
torssuchasCR1andCR3onleukocytes,thusenhancingphagocyticcapacityandtherespiratoryburst[28].Further,C5atriggeredtheproductionofsuperoxideanionandPGE2fromresidentandelicitedmouseperitonealmacrophages[29],aswellasTNFandIL-1fromhumanandmousemacrophagepopulations[30,31].Itisnotsurprisingthatgivensuchpleio-tropic,proinflammatoryeffects,theC5aRisanessentialme-diatorofinflammationanddiseaseprogressioninthecollagen-inducedarthritis(CIA)model[32].InCIAinmice,C5aRablationpreventedtherecruitmentofneutrophils,Tcells,andmacrophagestojoints,decreasedthelevelsofinflammatorymediators(suchasIL-1andTNF)andchemoattractants(includingMIP-1␣,MIP-2␣,andepithelial-derivedneutro-phil-activatingfactor-78),andreducedjointinflammation,boneerosion,andpawswelling[32].Similarly,systematicadministrationofanti-C5amAbpreventeddiseaseonsetandamelioratedestablisheddiseaseinthesamemousediseasemodel[33].C5ahasalsobeenimplicatedasamajormediatorofhumaninflammatorydiseases,includingsepsis,acutelunginjury,andasthma/allergy[34].Forexample,sepsistriggerscomplementactivation,leadingtoelevatedlevelsofcomple-mentproducts,includingC5a,inhumansandinanimalmodels[35,36].InsupportofacentralroleforC5ainsepsispathol-ogy,blockadeofC5aactioninexperimentalsepsishasprovenbeneficial.Administrationofarabbitanti-humanC5aantibodyincreasedthesurvivalrateinaprimatemodelofsepsis[37].Similarly,anti-C5atreatmentinaratmodelofsepsisamelio-ratedtheprogressionofmultipleorganfailure,whichisasso-ciatedwithhighmortalityrate[38].
TheFPRfamily
Peptidereceptors
ThecomplementreceptorC5aR
ThecomplementcomponentC5aactsasapotentneutrophilandmonocytechemoattractantviatheGPCRC5aR/CD88[27].Italsoup-regulatestheexpressionofothercomplementrecep-
TheFPR1,aswellastherelatedfamilymembersFPR-like(FPRL)1and-2,areexpressedinaregulatedmannerinmacrophagesatmRNAandproteinlevel[39–42].FPR1trig-gerscellularlocomotionuponrecognitionofN-formylatedme-
Fig.2.OverviewofGPCRfunctioninmacrophages.GPCRsregulatediversemacrophagefunctionsincludingcell-cellcontact,survival,chemotaxisandactivation(e.g.,inflammatorymediatorproduction).
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thioninefrombacterialproteins.TheclassicFPR1agonist,fMLP,hasamuchhigheraffinityforFPR1thanFPRL1,andectopicexpressionstudiessuggestthatFPRL2doesnotrec-ognizethisligand[43–45].However,anendogenouspeptideligandforFPRL2wasidentifiedrecently[46],anditisnowclearthatFPR1andFPRL1canalsodetectnonformylatedbacterialproteins[47],aswellasendogenousligandssuchasannexin1[48],serumamyloidA[49],andamyloid-peptideof42residues[50].Giventheelevatedproductionofsuchendogenousligandsinchronicinflammatoryandneurodegen-erativediseases,targetingoftheFPRfamilymayreduceleukocyterecruitmentandinflammationinsuchsettings[43].FPRsalsoregulatetheprocessofmacrophageactivation;fMLPinducedtheexpressionofinducibleNOsynthetase(iNOS)andproductionofNOinmouseperitonealmacrophages[51]andthesecretionofIL-1␣,IL-1,andIL-6inhumanPBMC[52].TheimportanceofFPRinantimicrobialresponsesishigh-lightedbytheincreasedsusceptibilityofFPR-deficientmicetoListeriamonocytogenes[53].
WhilstFPRantagonistsmayhaveapplicationsasanti-inflammatoryagents,agonistsoftheFPRfamilymayhaveunexpectedapplicationsintheHIVfield.Thechemokinereceptors,CXCR4andCCR5,arecoreceptorsusedbymac-rophage-tropicHIVstrainstogaincellularentry[54,55].Individualswhoarehomozygousfora32-bpdeletionintheCCR5genelackfunctionalsurfaceCCR5yethaveanormalphenotypeandarerelativelyresistanttoHIV-1infection,thushighlightingtheimportanceofthisreceptorinHIVpathogen-esis[56,57].ActivationofFPRorFPRL1byfMLPinhumanmonocytes/macrophagesrapidlyinducedserinephosphoryla-tionandheterologousdesensitizationofCCR5andCXCR4[58,59].Further,fMLPreducedthefusionandinfectionofparticularstrainsofHIV-1inmacrophagesbycompromisingtheabilityofCCR5andCXCR4toactasHIV-1coreceptors[59];thereforeFPRagonistscouldbeexploredinthefutureasanapproachtotargetHIVspread.
Theprotease-activatedreceptor(PAR)family
andsmoothmusclecellssuchasatheroscleroticlesions[62,63].PAR-1nullmiceexhibiteddecreasedsecretionoftheproinflammatorymediatorsIL-1,IL-6,andmatrixmetallopro-teinase(MMP)-13,aswellasreduceddiseaseseverityinamousearthritismodel[64],whilePAR-2nullmiceshoweddiminishedcontacthypersensitivityresponsesandwerecom-pletelyresistanttoadjuvant-inducedarthritis[65,66].
Neuropeptidereceptors
Rodentandhumanmacrophagesexpresstheneurokinin-1receptor(NK-1RorTACR1),whichsignalsinresponsetoneuropeptidesubstanceP(SP)[67,68].SPisdistributedwidelywithinthecentralandperipheralnervoussystems,whereitregulatesneuronalcellsurvivalandneurotransmission[69].Italsomediatesproinflammatoryeffectsonanumberofinflammatorycells,includingmacrophages.SPinducedtheproteinexpressionofIL-1,TNF,andIL-6inhumanbloodmonocytesandhumanmonocyte-derivedmacrophages[70,71]andincreasedproductionofreactiveoxygenspeciesandPGD2secretionfromguineapigalveolarmacrophages[72].Expres-sionofNK-1RandSPproteinwasinducedinratandhumanmacrophagesinresponsetoLPS[67,68,73],suggestingtheexistenceofanautocrinepathway.
AswithSP,neuropeptideY(NPY)alsoperformsimmuno-modulatoryfunctions.Intheperipheralnervoussystem,NPYisconcentratedinthesympatheticdivision,isreleasedfromsympatheticnerveendingsandisthoughttoprovideanavenueforneuroimmunecrosstalk[74].SecondarylymphoidtissuessuchasthespleenarerichlyinnervatedbysympatheticnerveswhichcontainNPY[75]andthereisphysicalevidenceofsynapsesbetweenthenerveendingsandleukocytes[74,76].ExpressionoffunctionalNPYreceptorsoncellsoftheimmunesystem,includingmacrophages,hasbeenconfirmed[77,78]andNPYmodulatedseveraleffectorfunctionsofthemacro-phages[77,79,80].Forexample,DelaFuenteetal.[77]demonstratedthatNPYstimulatedadherencetosubstrate,chemotaxis,ingestionoflatexbeadsandproductionofsuper-oxideanioninmurineperitonealmacrophages.
Endothelial(ET)receptors
ThePARsareafamilyofGPCRsthatareactivateduponproteolyticcleavageoftheiraminoterminalexodomain.Thisunmasksanewaminoterminalwhichactsasatetheredligandtoactivatethereceptor.Differentiationofhumanmonocyteswasassociatedwithdifferentialexpressionoffunctionallyac-tivePARs,particularlyPAR-1andPAR-2,whichmediatedistinctregulatoryfunctionsininflammation[60].Inhumanmonocytes,PAR-1wasthemostabundantlyexpressedPAR,whilstPAR-3wasexpressedweakly.InvitrodifferentiationofhumanmonocytestomacrophagesbytreatmentwithGM-CSForCSF-1coincidedwithamarkedincreaseintheexpressionofPAR-1,-2,and-3atthemRNAandproteinlevel[60].Throm-bin-inducedactivationofPAR-1and-2inhumanperipheralmonocytesormacrophagesinducedthereleaseoftheproin-flammatorymediatorsMCP-1(CCL2)andIL-6[60],whilestimulationofPAR-2byPAR-2receptor-activatingpeptidesinhumanperipheralbloodmonocytesincreasedtheproductionofIL-1,IL-6,andIL-8[61].SeveralstudiesimplicatePARsasregulatorsofinflammatorydisease.PAR-1isabundantinthesynovialliningofrheumatoidarthritis(RA)andosteoarthritispatientsandishighlyexpressedinregionsrichinmacrophages
ET-1,thepredominantisoformoftheETpeptidefamilythatincludesET-1–4,regulatescellfunctionthroughtheGPCRs,ETreceptorsubtypeA(ETAR)andETBR.ET-1isproducedpredominantlybyendothelialcellsinthecardiovascularsys-temandisapowerfulvasoconstrictorandstimulatorofsmoothmusclecellproliferation[81,82].Inaddition,ET-1modulatesimmunecellfunctionduringinflammatoryresponses[83,84].InvitrostimulationofmurineperitonealmacrophageswithET-1inducedcyclooxygenase2(COX-2)mRNAexpressionandPGE2production[85].ET-1canalsoinducethesecretionofproinflammatorycytokinesbymacrophages.Forexample,ET-1treatmentofthemacrophagecelllineJ774.2increasedTNFsecretionviatheETAR[86].Inhumanmonocytes,ET-1triggeredTNFproduction,aswellasothercytokines,includingIL-8,GM-CSF,IL-1,andIL-6[87].ET-1canalsoinfluencetheproductionofsuperoxidesbymacrophages;ET-1primedO2–productionfromrabbitalveolarmacrophages[88].Finally,ET-1,aswellasET-2,elicitedMMP-2and-9productionfromhumanmonocyte-derivedmacrophageswhencoculturedwith
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breastcancercells[89].GiventheelevatedexpressionofET-1andtheETreceptorsinhighgrade,aggressivemetastaticbreastcancer[89–91],tumor-associatedmacrophagesmaypromotetumorspreadviathispathway.
NotonlydoesET-1regulatemacrophagefunction,butitisalsosecretedbythiscelltype;murinebonemarrow-derivedmacrophagesproducedET-1uponchallengewithgram-nega-tiveandgram-positivebacteria[92]andLPS[93].ClinicalobservationsinhumansandanimalmodelsofinflammationsuggestthatmacrophagesareanimportantsourceofET-1duringinfectionandinflammation[92,94–98].PeripheralbloodmonocytesfromsepticpatientsexpressedsignificantlyhigherlevelsofET-1mRNAincomparisonwithhealthysub-jects[94].Inaddition,Kupffercells(macrophagesresidingintheliver)releasedET-1inexperimentalmodelsofendotox-emia[95].Thesestudiesformpartofagrowingbodyofliteraturewhichsuggestaninvolvementofmacrophage-derivedET-1ininflammation.Indeed,theETsystemhasbeenpursuedasatargetforthetreatmentofinflammatorycardiovasculardiseaseandchronicobstructivepulmonarydisease[89–91,99–104].
Lipidreceptors
Theplatelet-activatingfactorreceptor(PAFR)
SeverallipidGPCRagonistsareregulatorsofmonocyte/mac-rophagefunction.PAF,whichisproducedandsecretedbyplatelets,neutrophils,eosinophils,monocytes,andmacro-phages[105,106],triggeredchemotaxisofmurineperitonealmacrophagesinadose-dependentmanner[107].Indeed,thePAF/PAFRsystemhasbeenimplicatedasamediatorofmonocyterecruitmentduringtheonsetofatherosclerosis[108].Inadditiontoregulatingmacrophagemigration,thePAFRmodulatesmacrophageactivation.PAFantagonistsinhibitedLPS-regulatediNOSmRNAexpressionandNOproductioninmurinemacrophagesandratKupffercells,implyinganinvolvementofautocrinePAFinLPSresponses[109–111].Furthermore,aPAFantagonistreducedthetoxicityofsystemicadministrationofendotoxinand/orlivebacteria[112–114].
AlthoughthePAF/PAFRsystemcontributestoexcessivehostinflammatoryresponses,itisalsocriticalforphagocytosisandeffectivepathogenclearance.PAFR-deficientmicehadenhancedbacterialloadinthelungsfollowingpulmonarychallengewithKlebsiellapneumoniaeandsuccumbedmorerapidlythanwild-typemice[115].Thisprotectiverolemaybepathogen-specific;thePAFRdidnotregulatebacterialloadsordiseaseseverityduringinfectionwithanotherlungpathogen,Mycobacteriumtuberculosis[116].Conversely,thePAFRisactuallyexploitedbyStreptococcuspneumoniaetoenablecel-lularinvasion[117].Apartfrominfectiousdisease,thePAF/PAFRhasbeenimplicatedinthepathologyofseveralinflam-matorydiseasesincludingthrombosis,allergicdisorders,ana-phylacticshockandacutelunginjury,aswellasmetastaticdisease[118,119].
TheleukotrieneB4receptor(LTB4R)
LTB4,anarachidonicacidderivative,actsviathetwoGPCRLTB4Rs,LTB4R1(BLT1)andLTB4R2(BLT2)[120,121],to
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stimulatemacrophage,neutrophil,eosinophil,andmastcellchemotaxis[122,123].MastcellsareamajorsourceofLTB4[124],butitisalsosecretedbyhumanalveolarmacrophages[125]andmurineperitonealmacrophages[126],suggestingtheexistenceofanautocrinepathwayinthislineage.Theimpor-tanceofLTB4-mediatedcellularrecruitmentishighlightedbythefailureofinflammatorycellstoinfiltrateintojointsandinitiateCIAinLTB4RϪ/Ϫmice[127].Inaddition,inhibitorstudieshaveimplicatedLTB4Rinmonocyterecruitmentandfoamcellformationinamousemodelofatherosclerosis[128].LTB4alsoinitiatesantimicrobialresponsesduringpathogenicchallenge.AswiththePAFR,LTB4appearedtobeacriticalfactorforthephagocytosisofK.pneumoniaebyalveolarmac-rophages[129,130].Indeed,PAFandLTB4havemanyover-lappingbiologicalactivities,whichmaybeexplainedtosomeextentbytheobservationthatinneutrophilsatleast,PAFactionwasmediatedpartlyviaautocrineLTB4[131].Exoge-nousLTB4activatedtheNADPHoxidasesysteminalveolarmacrophages[132],aswellasNOandTNFproductionandparasitekillinginTrypanosomacruzi-infectedmurinemacro-phages[133],indicatingthattheLTB4Rcanactivatemultipleantimicrobialpathways.
TheEPfamily
PGE2,asmalllipidmediatorthatregulatesdiverseprocessesincludingplateletaggregationandimmunefunction,ispro-ducedbyfibroblasts,somemalignantcellsandmacrophages[134].InvivoadministrationofPGE2resultsinanacuteinflammatoryresponsecharacterizedbypain,edema,andleu-kocyteinfiltration[135].Indeed,PGE2isamajormediatorofpathologyininflammatorydiseasessuchasRAandosteoar-thritis[136–138],andCOX-2,akeyenzymeinthePGE2biosyntheticpathway,hasbeentargetedextensivelyinthera-peuticapplicationsininflammatorydiseases[139].PGE2cansignalthroughfourEPs,EP1–4,allofwhichareGPCRs[140,141].TargeteddisruptionofeachoftheseEPshasdemon-stratedthatPGE2mediatesdistinctfunctionsdownstreamofeachreceptor:neuronalfunctionsviaEP1;femalereproduc-tion,vascularhypertension,andtumorigenesisviaEP2;fever,gastricmucosalprotection,painhypersensitivity,kidneyfunc-tion,andantiallergicresponseviaEP3;andductusarteriosusclosureandinflammation-associatedboneresorptionviaEP4[142–149].
PGE2isalsoimplicatedinthedevelopmentandmainte-nanceofTh2responses.PGE2generallysuppressesinflamma-torycytokineproductionfrommonocytesandmacrophages[150–154].Infact,theeffectsareselective;PGE2inhibitedtheproductionoftheTh1-promotingcytokineIL-12butam-plifiedIL-10productionfromhumanandmousemacrophagesrespectively[154,155].Similarly,Kurodaetal.[156]showedthatpretreatmentofmurinesplenocyteswithPGE2suppressedtheproteinexpressionoftheTh1-associatedchemokineIFN-inducibleprotein-10andenhancedproductionofmacrophage-derivedchemokine/CCL22,aligandfortheTh2cell-expressedchemokinereceptorCCR4.Sucheffects,aswellasdirectactiononTcells[157–160],resultinapolarizedTh2responseinmanyTh1/Th2-biaseddiseasemodels.
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Theendothelialdifferentiationgene(EDG)family
MembersoftheEDGfamilyareactivatedbythelipidmedia-torslysophosphatidicacid(LPA)andsphingosine-1-phosphate(S1P)whichareprimarilyderivedfromactivatedimmunecells,includingplatelets,monocytes/macrophages,neutrophils,eo-sinophilsandmastcellsduringbloodclottingandwoundhealing[161–163].LPAstimulateswoundhealingbyinducingendothelialcellstoexpressadhesionmoleculesandproducecytokineswhichrecruitmacrophagestothesiteofthewound,therebymediatingtheinteractionofmacrophageswithendo-thelialcells[164–166].However,humanmonocytesandmac-rophagesalsoexpressseveralEDGreceptorsincludingEDG1,-2,-4,-5,and-8[167],suggestingthatLPAregulatesmacro-phagefunctiondirectly.Certainly,ratalveolarmacrophagesrespondedtoLPAandS1PbyproducingO2–atlevelscomparablewiththoseinducedbyLPSorfMLP[167].LPAisalsoimplicatedinregulatingmacrophagesurvival.ThePI-3K-Aktpathwayisrequiredformacrophagesurvival[168]andLPAactivatedthePI-3Kpathwaytoprovideasurvivalsignalinmurineperitonealmacrophagesduringserumdeprivation[169].
TheEGFfamily
tientswheretheligandsforthesereceptors,chondroitinsul-fatesandCD55(decay-acceleratingfactor),arealsopresent[178].EMR2andCD97contributetotherecruitmentandretentionofmacrophagestosynovialtissueinRA[178].EMR3isexpressedatthehighestlevelsinneutrophils,monocytesandmacrophages.Humanmonocyte-derivedmacrophagesandactivatedhumanneutrophilsboundEMR3[179],suggestingtheligandregulatescell-cellinteractionsinthemyeloidlin-eage.However,aswithothermembersoftheEMRfamily,littlefunctionalinformationiscurrentlyavailable.
Novelmacrophage-specificGPCRs
TheEGFfamilyofGPCRs,whicharethoughttobeinvolvedinregulatingcell-cellinteractions,consistsofsixmembersinhumans:EMR1–4,CD97andEGF-TM7-latrophilin-relatedprotein(ETL).MicelackfunctionalEMR2and-3genes.WiththeexceptionofETL,whichisexpressedinsmoothmuscle,allofthefamilyisexpressedonhematopoieticcells.Further,EMR1–4expressionisrestrictedtothemyeloidlineage.ThefoundingmemberoftheEGF-TM7family,EMR1,originallynamedF4/80,isadefinitivemarkerofmurinemacrophagesandisexpressedonavarietyofmacrophagesubsetsincludingliverKupffercells,residentbonemarrowmacrophages,thymiccorticalmacrophages,splenicredpulpmacrophages,lymphnodemedullarymacrophages,Langerhancells,microglialcellsandsomeCD8-negativemyeloiddendriticcells(DC)[170–172].AroleforEMR1intheadaptiveimmuneresponsewasdemonstratedrecently;Linetal.[173]showedthatEMR1wasessentialforthedevelopmentoffunctional,CD8-positive,an-tigen-specificregulatoryTcells(Treg),whicharenecessaryfortolerance.However,aligandforEMR1hasnotbeenidentifiedanditsexactroleinregulatingmacrophagefunctionremainspoorlydefined.Inhumans,EMR2andCD97wereidentifiedasreceptorsforcellsurfacechondroitinsulfate[174],suggestingthattheligandforEMR1maybeaproteoglycan.GivenitsroleinthedevelopmentofTreg,theEMR1ligandmaybeex-pressedonthiscelllineage.
EMR4,alsoknownasF4/80-likereceptor(FIRE),ismostsimilartoEMR1andisalsoexpressedpredominantlyontissuemacrophagesinthemouse[175].Itsproteinexpressionisup-regulatedduringmacrophageactivation[175]butlikeEMR1,itsfunctionisunknown.EMR2expressioninhumansisalsorestrictedtomyeloidcellsincludingmonocytes,mac-rophages,DCandgranulocytes.CD97istheclosestfamilymembertoEMR2sharedbymice.However,unlikethere-strictedexpressionofEMR2,CD97isexpressedonabroadrangeonleukocytes[176,177].EMR2andCD97arehighlyexpressedonmyeloidcellsinthesynovialtissueofRApa-
Recentexpression-profilingstudieshaveenabledtheidentifi-cationofseveraltissue-specificgenes.OneexampleistheGenomicInstituteofNovartisResearchFoundationSymatlasdatasetthatcharacterizedgeneexpressioninapanelofhumancelltypesincludingprimarymonocytesandotherleukocytepopulations(ref.[180];http://symatlas.gnf.org/SymAtlas/).Thisdatasethasrevealedtheexistenceofseveralmacrophage-enriched,orphanGPCRsofunknownfunction.Theseincludethepurinergicreceptors(P2RY)5and-13andGPCR65.Acrossapanelofhumancelltypes,P2RY5andGPR65wereexpressedhighlyinseveralimmunecelltypesincludingDC,CD4ϩandCD8ϩTcells,CD56ϩNKcells,CD14ϩmono-cytesandCD33ϩmyeloidcells.P2RY13mRNAexpressionwasstrikinglyrestrictedtomacrophagesbeingexpressedonlyinwholebloodandprimaryhumanCD14ϩmonocytesandCD33ϩmyeloidcells(http://symatlas.gnf.org/SymAtlas/).Wehaveconfirmedthemacrophage-specificand/orregulatedex-pressionpatternsofsomeoftheseGPCRsinthemouse.Figure3AshowsthatP2RY6mRNAexpressionwaselevatedinapanelofprimarymousemacrophagesandmacrophagecelllinesascomparedwithlymphoidandfibroblastcelllines.InthecaseofP2RY5,weconfirmedthatmRNAexpressionisinducedduringmonocyte-to-macrophagedifferentiationinhu-mans(J.LattinandM.J.Sweet,unpublisheddata)andthatexpressionwasdown-regulateddramaticallybyLPSinprimarymousemacrophages(Fig.3B).Thedown-regulationin“clas-sicallyactivatedmacrophages”isconsistentwitharecentreportthatidentifiedP2RY5asaGPCRexpressedbyalter-nativelyactivated(M2)humanmacrophages[181].AlthoughligandsandfunctionsforsuchGPCRsareunknown,futurestudiesarelikelytoidentifyrolesininflammationandimmu-nity.
AdditionalcomplexityofGPCRexpressionandfunctioninmacrophagebiology
ManyoftheGPCRsdescribedabovehaveoverlappingbiolog-icalactivitiesonmacrophages.Despitetheapparentredun-dancy/overlapintheirbiologicaleffectsonmacrophages,geneknockoutstudieshavegenerallydemonstratednonredundantrolesforGPCRsininflammationandimmunity(e.g.,C5aR[32],PAFR[115],EMR1[173],EP2and-4[182,183],aswellasthechemokinereceptorsnotreviewedhere).Thisisoftenthecaseeveninthesamemodel,forexample,thecommonlyusedCIAmodelinmice.Generally,suchstudieshaveas-sessedhowasingleGPCRagonistaffectsbiologicalresponses.However,tissuemacrophagesandrecruitedmonocytesinaninflammatorysettingarelikelytoencountermultipleagonists
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Fig.3.ExpressionanalysisofP2RY5and-6inmousemacrophages.Quan-titativereal-timePCRanalysiswasusedtoassessthemRNAlevelsof(A)P2RY6inapanelofmurinecelltypes,includingprimarybonemarrow-derivedmacrophages(BMM),macrophagecelllines(RAW264.7,WR19M),lympho-blastcelllines(EL4andMOPC)andfibroblastcelllines(NIH3T3andL929),and(B)P2RY5inbonemarrow-derivedmacrophagesculturedinthepresenceofCSF-1overaLPStime-course(0–21h).LevelsofmRNAaredisplayedasrelativetothehousekeepinggenehypoxanthineguaninephosphoribosyltrans-ferase(HPRT;meanoftriplicatesϩSD;representativeofthreeindependentexperiments;A)ornormalizedtotheuntreatedcontrolacrossthreeindepen-dentexperiments(meanϩSEM;B).
andinvitrostudiesusingcombinationsofGPCRagonistswouldbemorelikelytoreflecttheinvivoenvironment.InvitrostudiesthatassesscombinatorialeffectsofGPCRagonistsmayidentifysynergistic,antagonistic,ortrulyredundanteffectsofGPCRligands,whichwouldnototherwisebeapparent.TheantagonisticeffectofFPRandFPRL1ligandsonCCR5andCXCR4responsesrepresentsoneexampleofsuchinterplay[59].Alternatively,theindividualGPCRsmightfunctionindistinctstagesoftheinflammationprocess,effectivelyactinginapathwaythatcanbeblockedatmultiplelevels.
Anadditionallevelofcomplexityisapparentatthelevelofgeneregulation.Recentgenome-wideanalysisoftranscriptionstartsitesusingcapanalysisofgeneexpressionhasdemon-stratedthatalternativepromoteruseisappliedextensively[184].Indeed,severalGPCRsincludingP2RY5,ETBRandEDG1,appeartousemultiplepromoters/transcriptionstartsites,aphenomenonthatislikelytoimpactontissue-specificexpressionandfunction.AlternativesplicingalsooccursinsomeGPCR-encodedgenes.Forexample,multiplealterna-tivelysplicedformsofEMR1lackthetransmembrane-span-ninghelicesandpresumablyencodesoluble,secreteddomi-nant-negativeformsofthereceptor.AlternativelysplicedformsoftherelatedGPCRs,CD97andEMR2,havevariablenum-bersofEGFdomainsintheextracellularregion.InthecaseofEMR2,onlythefull-lengthisoformwasabletomediatecell-cellinteractionsthroughchondroitinsulfate[174].Thus,reg-22
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ulationofalternativesplicingislikelytoimpactonthefunctionofseveralmacrophage-expressedGPCRs.
EXPRESSIONANDFUNCTIONOFGPCRSIGNALINGCOMPONENTSINMACROPHAGES
Macrophage-enrichedexpressionofGPCRsignalingcomponents
GiventhediversityofGPCRsinmacrophages,itisperhapsnotsurprisingthatGPCRsignalingcomponentsareexpressedatelevatedlevelsinthesecells.AsidefromtheirfunctioninsignalinginresponsetothemanyGPCRsexpressedbythislineage,anemergingliteratureisalsodocumentingnovelrolesforthesesignalingcomponentsinGPCR-independentre-sponsesinmacrophages.Here,weidentifythoseGPCRsig-nalingmoleculesthatarehighlyexpressedinmacrophagesandfocusontheirroleinalternativepathwaysofcellactivation,withparticularemphasisonTLRsignaling.
G-proteins
G-protein-mediatedsignaltransductionisafunctionallyver-satilesystemasaresultofitsmodulararchitectureandtheexistenceofnumeroussubtypesofG-proteins.The␣-subunitsaredividedintofourfamilies(G␣s,Gmultiple␣i/G␣o,Gsubtypes.␣q/G/G␣11andG␣12␣13)andeachfamilycontainsUnlikethe␣-subunits,the␥-subunitsareassembledfromarela-tivelysmallrepertoire:five-subunitsand12␥-subunits.SeveralG-proteinsshowrestrictedexpressionatthemRNAlevel;forexample,GspecificwhileG␣O1,G␣z,G␣14,G␥7,andG␥13arebrain-␣T1/2andG3arerestrictedtothevisualsystem(http://symatlas.gnf.org/SymAtlas/).
Primaryhumanandmousemacrophagesexpresselevatedlevelsofthepertussistoxin(PTx)-sensitiveGsubtypes(ref.[185];http://symatlas.gnf.org/SymAtlas/).␣i2andGSeveral␣i3linesofevidencesuggestthatinmacrophages,PTx-sensitiveG-proteinsregulatenotonlyGPCRsignaling,butalsoTLRsignaling.JakwayandDeFranco[186]firstshowedthatpre-treatmentofthemacrophagecelllineP388D1withPTxre-ducedtheproductionofIL-1inresponsetoLPS.PTxalsoimpairedLPSresponsesinhumanmonocyticU937cells.Fur-ther,LPSstimulationcausedGimplicatingthisG-protein␣asi2phosphorylationinthesecells,aplayerinLPSsignaling[187].Inmouseperitonealmacrophages,PTxinhibitedLPS-dependentNOproductionbutamplifiedTNFproteinproduc-tion[188],althoughothersreportednoeffectofthisinhibitoronTNFsecretion[189].Atthelevelofsignaling,PTxreducedLPS-mediatedactivationofp38,ERK1/2andAP-1,withoutaffectingNF-Bactivation[190–192].GeneticapproachesalsosupportaroleforPTx-sensitiveG-proteinsinTLR-medi-atedresponses.Forexample,LPS-inducedTNF,IL-10andthrombaxaneB2proteinproductionwasreducedinperitonealmacrophagesderivedfrommicelackingGWhethersucheffectsaredependentonGPCRs␣i2orGis␣i1/3[193].unknown,butatleastonestudyhasimplicatedtheGPCR,CXCR4,aspartofaCD14-independentLPSreceptorcomplex[194].WhilePTx-sensitiveG-proteinscanregulateGPCRandTLR
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signalinginmacrophages,PTx-insensitiveG-proteinsappeartooccupyamoreconventionalsignalingrolebycouplingseveralchemotacticGPCRs[e.g.,CXCR2,C5aR,C3aR,FPRandtheIL-8receptor(IL-8R)]toactivationofNF-B[195–198].Inmanyofthesecases,G␣15/16wasimplicatedasaspecificplayerandafunctionforthisPTx-insensitiveG-proteininGPCRsignalinginmacrophagesissupportedbyitselevatedexpressioninprimaryhumanCD14ϩmonocytesandCD33ϩmyeloidcells(http://symatlas.gnf.org/SymAtlas/).The-subunitsG1andG2L1[alsoknownasreceptorforactivatedCkinase1(RACK-1)]arealsoexpressedhighlyinprimarymousemacrophages,primaryhumanCD14ϩmono-cytesandotherleukocytepopulations(http://symatlas.gnf.org/SymAtlas/),andevidenceexistsforrolesinnon-GPCRsignal-ing.Inhumanembryokidney(HEK)293cells,G1interacteddirectlywithhistonedeacetylase(HDAC)5[199],amemberoftheHDACfamilywhichregulatesgeneexpressionbymodify-inghistoneproteinsandtranscriptionfactorspost-translation-ally.HDACshavebeenreportedtoregulateLPS-inducedproinflammatorygeneexpressioninmacrophages[93];thus,G1mayimpactonTLRsignalingbyregulatingHDAC5function.G2L1alsohasrolesbeyondregulationofGPCRsignaling;itmediatedtherecruitmentofSTAT1andSTAT3totheIFN-␣/andthetyrosinekinaseinsulin-likegrowthfactorreceptor1(IGFR-1)receptors,respectively[200–202].
mainandhavepoorlydefinedfunctions[203,204].Inadditiontoitswell-recognizedroleinactivatingtheERKandAKTpathways,thetyrosinekinaseIGFR-1signalsviathehetero-trimericG-proteinG␣i2[212,213].RGS19[alsoknownasG␣-interactingprotein(GAIP)interactsspecificallywiththePDZ-containingprotein,GAIP-interactingprotein,C-terminus(GIPC)[214].InteractionoftheRGS19/GIPCheterodimerwiththeIGFR-1consolidatesIGF-1signalingtoMAPKactivation[215].RGS19andGAICcanalsoformacomplexwiththenervegrowthfactorreceptor,TrkA[216],althoughitremainsunclearhowthiscomplexaffectssignalingthroughthesere-ceptors.AlthoughfunctionalstudiesaboutRGS19havenotbeenperformedinmacrophages,IGF-1canstimulateprolifer-ationofmousemacrophagesandtheirprogenitors[217,218].Thus,RGS19islikelytoregulateIGF-1signalinginmacro-phages,andgiventhemacrophage-enrichedexpressionofmanyRGSfamilymembers,otherfunctionsinthislineagearelikelytoexist.
GRKs
TheGRKfamilyconsistsofsevenmembersandcanbegrouped,accordingtohomology,intotherhodopsin/visualGRKgroup(GRK1and-7),GRK2and-3group(alsoknownasthe-adrenergicreceptorkinase1and2,respectively)andGRK4group(GRK4,-5,and-6)[219,220].AlthoughGRK2,-5and-6arereportedlyexpressedubiquitouslyinmiceandhumans,theyareexpressedhighlyatmRNAlevelsinmonocytesandmacrophages[221](http://symatlas.gnf.org/SymAtlas/),andGRK2and-6proteinlevelsareinducedduringmonocytedifferentiation[222].ArraydatasuggestthatGRK2and-6mRNAexpressionisdown-regulatedbyLPSinbonemarrow-derivedmacrophages(http://symatlas.gnf.org/SymAtlas/).Inaddition,severalstudieshavedocumentedreg-ulatedexpressionofGRKsduringinflammatoryresponses.ProteinexpressionofGRK2and-5waselevatedinthelungsofIL-1-treatedrats[223]whileoxygenradicalsandtheinflammatorycytokines,IL-6andIFN,reducedGRK2proteininhumanTlymphocytesandhumanPBMC,respectively[224,225].Furthermore,GRK2and-5proteinexpressionwasdown-regulatedbyLPSinpolymorphonuclearneutrophils,therebyaugmentingchemokineresponsiveness[226].InRApatients,GRK2and-6proteinlevelsinPBMCweredecreasedmark-edly[225].SimilareffectsonGRK2and-6expressionwereapparentinmousesplenocytesduringallphasesofthemousemodelofmultiplesclerosis,experimentalautoim-muneencephalitis(EAE)[227].Grk2heterozygousknock-outmiceshowedanearlieronsetofEAEwhichwasasso-ciatedwithanincreaseinearlyinfiltrationofTcellsandmacrophages[228].LocomotionofTcellsderivedfromGrk2-/ϩmicewasenhancedinresponsetochemokinessuchasMIP-1␣andMIP-1[229].Thus,reducedGRKexpressionininflam-matorydiseasesislikelytoenhanceleukocyteinfiltrationanddiseaseprogression.
AswiththeRGSfamily,GRKshavefunctionswhichareindependentofGPCRdesensitization[230,231].First,GRKsareabletophosphorylatenonreceptorsubstratessuchastu-bulin[232],synucleins[233]andphosducin[234].Inaddition,GRKsmodulatesignalinginaphosphorylation-independentmannerbyinteractingwithproteinsinvolvedinsignalingand
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RegulatorsofG-proteinsignaling(RGS)
TheRGScontroltherateofGTPhydrolysisontheG␣subunitofheterotrimericG-proteins.AlongwithGRKsandarrestins,theyregulatethedurationofsignalingdownstreamofGPCRs.TheRGSfamilyisdiverse,ranginginsizefrom17kDato160kDaanddisplayingwidelyvariableandregulatedexpressionpatterns[203].Thefamilycontains30members,allofwhichshareacommonRGSdomainthatisresponsiblefortheirGTPase-activatingactivity.MostRGSproteinshaveGTPase-activatingactivityspecificfortheG␣iandG␣qsubfamiliesofthe␣-subunits.SomeRGSnotonlyregulateG-proteinsignal-ingthroughcontrollingG␣GTPhydrolysisbutcanalsofunc-tionessentiallyaseffectorantagoniststhroughcompetitiveinhibitionofeffector-G␣-proteininteractions[203,204].
Ourownunpublishedmousemicroarraydata,aswellashumanandmousesymatlasmRNAexpressiondata(http://symatlas.gnf.org/SymAtlas/),indicatethatRGS1,-2,-10,-18and-19areexpressedinamacrophage-enrichedmannerorarestronglyregulatedbyLPS.Inaddition,Hausmannetal.[205]showedthatLPSandTNFincreasedRGS7mRNAlevelsmarkedlyinthemacrophage-likecelllineRAW264.7[205].RGS1,-2,-3,-4,and-13regulatechemokine-mediatedhom-ingofBcellswhileRGS16controlsTcellmigration[206–210].AfunctionalroleforRGS1indesensitizingseveralchemotacticreceptorsinhumanmonocyteswasalsodemon-strated[211].However,itissomewhatsurprisingthatalmostnothingelseisknownofthefunctionofthisfamilyinmacro-phagebiology.
AnobviouspredictionisthatotherRGSfamilymembersalsoregulatemacrophagemigration,butthereisalsogrowingevidencetosuggestRGSmayperformGPCR-independentfunctions.First,severalofthelargerRGSproteinscontainlargeN-and/orC-terminalregionswhichflanktheRGSdo-
trafficking,includingPI-3Ks,guanosinetriphosphatase-activat-ingprotein,G␣qandG␥,ERKandAKT[235–240].BindingofGRK2or-3totheGGRKs[238,241],while␥complexinducesactivationoftheseselectivebindingofGRK2and-3toactivatedG␣qselectivelyinhibitsGcanalsoregulateERKactivation.␣qsignaling[242,243].GRKsTcellsderivedfromGRK2heterozygousmice,whichhavereducedexpressionofGRK2,hadsignificantlyenhancedERK1/2signalinginre-sponsetoCCR5ligandsinvitro[229].Furthermore,GRK5knockdownresultedinenhancedERKphosphorylationandIBkinase(IKK)-mediatedp105phosphorylationanddegra-dationinresponsetoLPSinthemacrophagecelllineRAW264.7.GRK5alsoboundtoandphosphorylatedp105,implyingthatp105phosphorylationbyGRK5negativelyreg-ulatesLPS-stimulatedERKactivation[244].Finally,GRKsalsoregulatesignalinginresponsetoTGF-andEGFinaGPCR-independentmanner[245,246].ThesedatasuggestthatGRKs,suchasGRK2,-5and-6,arelikelytomodulatemacrophagefunctionbyactingasregulatorycomponentswithinGPCRandnon-GPCRsignalingpathways.Theymaythereforecoordinatecrosstalkbetweenthemajorplayerswithinsuchpathways.
ARRBs
AlthoughARRBsarereportedtobeexpressedubiquitously,expressiondatageneratedbyourlaboratorysuggestthatal-thoughARRB1and-2mRNAandproteinaredetectableinarangeofcelltypes,ARRB1andinparticular,ARRB2areconstitutivelyexpressedathighlevelsinmouseandhumanmacrophages(J.LattinandMJ.Sweet,unpublisheddata).AswellasregulatingGPCRdesensitizationandthereforedown-streamsignaling,ARRBsalsoregulatemacrophagesignalinginaGPCR-independentmanner.Inmacrophages,growth,sur-vival,differentiationandactivationsignalsaregenerallytrans-ducedthroughthePI-3K,ERK,JNKandp38MAPKpath-ways,aswellastheNF-Bpathway.ARRBsregulatesignalingviaeachofthesepathwaysthroughtheirabilitytoactasadaptormoleculesintheassemblyofsignalingcomplexesandbyregulatingtheintracellularcompartmentalizationofthesecomplexes[247–249].
-ARR1and-2canbothcontributetoERK1and-2acti-vation.ActivationofanumberofGPCRsleadstophosphory-lationofERKwhichisindependentofG-proteinsyetdepen-dentonARRBs.Forexample,ARRB2wasrequiredforCXCR4,PAR-2,2-adrenergicreceptor,andangiotensinIIType1A-mediatedERKactivationviadirectbindingtocom-ponentsoftheERKpathwaysuchasSRCandRAF-1[250–256].Further,directbindingofARRBtoERKenhancedERKphosphorylationandtargetedittothecytosol[251,254].Activationofanumberofreceptortyrosinekinases,includingtheCSF-1receptor,whichisrequiredformacrophagesurvivalandproliferation[257],leadstoactivationofERK1/2[258].Therefore,itispossiblethatARRBsregulateERKsignaling,notonlyinresponsetoGPCRagonistsbutalsoinresponsetoreceptortyrosinekinaseligands.ThisiscertainlythecasefortheIGFR-1[259,260].Further,arecentpublicationdemon-stratedthatknockdownofARRB1resultedinincreased
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ERK1/2phosphorylationinresponsetoLPSinRAW264.7[244].
ARRB2,butnotARRB1,activatedJNK3signalingthroughitsabilitytoactasascaffold[261].AntagonismofangiotensinIIType1AinCOS-7cellsresultedinbindingofARRB2toJNK3andJNK3retentioninthecytosolinintracellularvesi-cles.TheinteractionamongJNK3,ARRB2andASK1resultedintheassemblyofsignalingcomplexesandenhancedphos-phorylationofJNK3.AconservedJNKdockingdomainintheC-terminalofARRB2(RRSLHL,aminoacids196–201)isrequiredforthisresponse[261,262].TheJNKsarecriticalforCSF-1-mediatedproliferationandsurvivalofmacrophages[263].WhetherARRB2regulatesCSF-1-regulatedJNKacti-vationinmacrophagesiscurrentlyunclear,butpreliminarystudiesinthislaboratoryhaveshownthattheJNKdockingdomainofARRB2doesindeedregulatemacrophagesurvival(J.LattinandM.J.Sweet,unpublisheddata).
ARRBsalsoregulatemacrophagesignalingthroughinter-actionwithNF-B,afamilyofproinflammatorytranscriptionfactors.ARRB1and-2interactedwiththeIB␣componentoftheNF-BsignalingcomplexinarangeofcelltypesincludingHEK293,HeLa,Jurkat,COS-7andTHP-1cells[264,265].ThisinteractioninvolvedtheN-terminalofARRB2andtheC-terminalofIB␣[264].OverexpressionofARRB1or-2inHeLacellsinhibitedTNF-inducedNF-Bactivation[265].Similarly,overexpressionofARRB2inHEK293cellsinhib-itedTNF-inducedNF-BDNAbinding,whileRNAinterfer-ence-mediatedknockdownofARRB2hadanopposingeffect[264].TheseinhibitoryeffectsofARRB2onNF-BactivationapparentlyoccurviathepreventionofIB␣phosphorylationanddegradation[264,265].Consistentwiththeseeffectsonsignaling,knockdownofARRB2enhancedthemRNAandproteinexpressionoftheNF-BtargetgenesIL-6andIL-8inresponsetoproinflammatorystimuli[264].
ArecentpublicationbyWangetal.[266]furtherdemon-stratedaroleforARRBsinTLR-mediatedmacrophageacti-vation.InresponsetoTLRorIL-1familyligands,TNFrecep-tor-associatedfactor(TRAF)6isauto-ubiquitinated,oligomer-izesandsubsequentlyinitiatesdownstreamsignalingevents,includingactivationofIKKandJNK[267,268].ARRB1and-2interactedwithTRAF6uponTLR4orIL-1RactivationandpreventedTRAF6auto-ubiquitination,oligomerizationandIKKactivation[266].Therefore,ARRBsactatmultiplelevelstoinhibitTLRsignaling.SuchdataarelikelytobeapreludetotheidentificationofotherGPCRsignalingmolecules(e.g.,G-proteins,RGSfamilymembers,GRKs)withintheTLRsig-nalingframework.
Insummary,anumberofGPCRregulatorymoleculesplayimportantrolesinmacrophagefunctionthroughregulationofsignaltransductiondownstreamofGPCRs,aswellasnon-GPCRs,suchasTLRs.TheabilityofGPCRregulatoryproteinstointeractwithcomponentsofmultiplepathwayswouldallowtheseproteinstomediatesignalingcrosstalk(Fig.4),thusenablingthecoordinationofapreciseandappropriatecellularresponse.Dysregulatedexpressionorfunctionoftheseregula-toryproteinsmaythuscontributetopathologyinacuteandchronicinflammatorydiseases.
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Fig.4.GPCRsignalingcomponentsregulateTLRsignaling.TheabilityofGPCRregulatoryproteinstointeractwithcomponentsofmultiplepathwaysallowsthemtomediatesignalingcrosstalkbetweenGPCRsandnon-GPCRs,suchastheTLRs.GrayarrowsdepictpotentialcrosstalkmechanismsincludingtransactivationofGPCRs,suchasCXCR4,inresponsetotheTLRagonistandGPCRregulatorycomponentmediationofsignalingdownstreamofnon-GPCRs,suchasNF-B,TRAF6,ERK1/2,JNKandp38[186–188,198,212,213,215,221,222,226,235,244,247,261,265,269].CrosstalkbetweenGPCRandnon-GPCRpathwaysenablesthecoordinationofpreciseandappropriatecellularresponses.Mal,MyD88adapter-like;TPL2,tumorprogressionlocus-2;TRIF,Toll/IL-1Rtranslationinitiationregiondomain-containingadaptor-inducingIFN-;IRAK,IL-1R-associatedkinase;IRF3,IFNregulatoryfactor3;MEKK1,MEKkinase1;ATF2,activatingtranscriptionfactor2.
CONCLUSIONS
GPCRsandtheirsignalingmoleculeshavediverseandcentralrolesinregulatingmacrophagefunction.Severalmacrophage-expressedGPCRshavebeentargetedintherapeuticap-proachesindiseaseareas,whichrangefrominfectiousdiseasetocancer.Here,wehavedocumentedotherpoorlycharacter-izedGPCRs,aswellasGPCRsignalingcomponentsthatarehighlyexpressedinmacrophagesorareregulatedduringmac-rophageactivation.Futurestudiesaboutsuchmoleculeswillprovidefurtherinsightintomacrophagebiologyandarelikelytoleadtonovelapproachesfortargetingmacrophage-mediateddisease.
wascovered,werenotcitedinthisreview.ThisworkwassupportedbyagrantfromtheNationalHealthandMedicalResearchCouncilofAustralia(ID301210).
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