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4/17/2016 Recognitionofdamageassociatedmolecularpatternsrelatedtonucleicacidsduringinflammationandvaccination

FrontCellInfectMicrobiol.20122:168. PMCID:PMC3539075
Publishedonline2013Jan8.Prepublishedonline2012Oct7.doi:10.3389/fcimb.2012.00168

Recognitionofdamageassociatedmolecularpatternsrelatedtonucleicacids
duringinflammationandvaccination
NaoJounai, 1,2KoujiKobiyama, 1,2FumihikoTakeshita, 1,2andKenJ.Ishii1,2,*
1
LaboratoryofAdjuvantInnovation,NationalInstituteofBiomedicalInnovation,Osaka,Japan
2
LaboratoryofVaccineScience,WPIImmunologyFrontierResearchCenter,OsakaUniversity,Osaka,Japan
Editedby:NelsonGekara,UmeaUniversity,Sweden
Reviewedby:DarioS.Zamboni,UniversidadedeSoPaulo,BrazilWillemVanEden,UtrechtUniversity,NetherlandsYanShi,UniversityofCalgary,
Canada
*Correspondence:KenJ.Ishii,LaboratoryofAdjuvantInnovation,NationalInstituteofBiomedicalInnovation,768SaitoAsagi,Ibaraki,Osaka5670085,
Japan.email:kenishii@biken.osakau.ac.jp

Received2012Sep7Accepted2012Dec13.

Copyright2013Jounai,Kobiyama,TakeshitaandIshii.

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Abstract Goto:

Allmammaliancellsareequippedwithlargenumbersofsensorsforprotectionfromvarioussortsofinvaders,who,
inturn,areequippedwithmoleculescontainingpathogenassociatedmolecularpatterns(PAMPs).Oncethese
sensorsrecognizenonselfantigenscontainingPAMPs,variousphysiologicalresponsesincludinginflammationare
inducedtoeliminatethepathogens.However,thehostsometimessuffersfromchronicinfectionorcontinuous
injuries,resultinginproductionofselfmoleculescontainingdamageassociatedmolecularpatterns(DAMPs).
DAMPsarealsoresponsiblefortheeliminationofpathogens,butpromiscuousrecognitionofDAMPsthrough
sensorsagainstPAMPshasbeenreported.AccumulationofDAMPsleadstomassiveinflammationandcontinuous
productionofDAMPsthatis,aviciouscircleleadingtothedevelopmentofautoimmunedisease.Froma
vaccinologicalpointofview,theaccuraterecognitionofbothPAMPsandDAMPsisimportantforvaccine
immunogenicity,becausevaccineadjuvantsarecomposedofseveralPAMPsand/orDAMPs,whicharealso
associatedwithsevereadverseeventsaftervaccination.Here,wereviewastherolesofPAMPsandDAMPsupon
infectionwithpathogensorinflammation,andthesensorsresponsibleforrecognizingthem,aswellastheir
relationshipwiththedevelopmentofautoimmunediseaseortheimmunogenicityofvaccines.

Keywords:PAMPs(pathogenassociatedmolecularpatterns),DAMPs(damageassociatedmolecularpatterns),
nucleicacids,metabolites,innateimmunity,DNAsensors,uricacid,vaccineadjuvant

Introduction Goto:

Hostcellsareequippedwithnumeroustypesofreceptorstodiscriminateselffromnonself.Whencellsare
attackedbyinfectiouspathogens,hostcellularreceptorssuchasTolllikereceptors(TLRs),nucleotide
oligomerizationdomain(NOD)likereceptors(NLRs),retinoicacidinduciblegeneI(RIGI)likereceptors
(RLRs),Ctypelectinreceptors,andothernonclassifiedreceptorsrecognizepathogenassociatedmolecular
patterns(PAMPs),smallmolecularmotifsconservedamongstmicrobes.ThroughtherecognitionofPAMP
molecules,innateimmuneresponsesareinduced,andinflammatorycytokinesareproducedthataidinthe
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eliminationofthepathogens.However,insomecircumstanceshostinflammatoryresponsescancausehostcell
deathleadingtotissueinjury,andthereleaseofhostcellularcomponentstotheextracellularenvironment.These
cellularcomponentscouldbeconsideredmessengersfordangertheyarealsoknownasdamageassociated
molecularpatterns(DAMPs).DAMPsincludelipids,sugars,metabolites,andnucleicacidssuchasRNAand
DNAspecies.DAMPsareimportantfortheeliminationofpathogens,butarealsoimplicatedinthedevelopmentof
autoimmunediseaseandchronicinflammatorydisease,andareusedasadjuvantsforvaccines.Interestingly,high
numbersofPAMPreceptorsalsorecognizeendogenousDAMPsandcanaugmentinflammatoryresponsesagainst
pathogens,whereascontinuousinflammatoryresponsesowingtoimpairedregulationofinflammatorysignaling
resultsinchronicinflammatorydiseaseorautoimmunedisease.Therefore,bipolarsensorsforbothPAMPsand
DAMPsappeartobethemostlyresponsiblefordysregulatedinflammation.Here,wedescribethevarioustypesof
DAMPsandtheirreceptors,withaspecialfocusonnucleicacidsasDAMPs.

LipidrelatedDAMPs Goto:

Lipopolysaccharide(LPS)

ArepresentativelipidfortheinductionofinflammatoryresponsesisLPS,aPAMPpresentingramnegative
bacteria.UponrecognitionbyTLR4,LPSpromotestheproductionofvariousinflammatorycytokinesfollowing
bacterialinfection(Table1).However,Shietal.reportedthat,TLR4alsorecognizesendogenousfattyacidsand
canactivateinflammatoryresponsesinadipocytesandmacrophages(Shietal.,2006).Inaddition,TLR4deficient
micedevelopedreducedinflammatorycytokineproductioninresponsetoahighfatdiet(Shietal.,2006).Previous
studieshaverevealedthatsaturatedfattyacidsarereleasedfromhypertrophiedadipocytesinthepresenceof
macrophages,andthatreleasedfattyacidsaresensedbymacrophagesinaTLR4dependentmanner,following
excessiveproductionofinflammatorycytokinessuchastumornecrosisfactor(TNF)(Suganamietal.,2007).
Becausetheproductionofproinflammatoryorinflammatorycytokinesisdysregulatedinobeseadiposetissues,
obesitycanbethoughtofasachronicinflammatorydiseasecausedbyfattyacidsactingasDAMPmolecules(Berg
andScherer,2005).

Table1
AssociationofPAMPorDAMPsensorswithautoimmunediseases.

Serumamyloidaprotein(SAA)

SomelipoproteinscanalsoactasDAMPmolecules.In1982,HoffmanandBendittrevealedthatthetreatmentof
micewithLPSofSalmonellatyphosaincreasedSAAlevels(HoffmanandBenditt,1982).Accordingtoseveral
studies,SAAfunctionsincholesteroltransportaswellasintheproductionofproinflammatorycytokines,
suggestingthatSAAisaDAMPmoleculethatrespondstobacterialendotoxins(Bankaetal.,1995Heetal.,
2003).Insupportofthis,increasedlevelsofSAAmaybecloselyrelatedtovariousdiseasessuchas
atherosclerosis,rheumatoidarthritis,andCrohn'sdisease(Chambersetal.,1983,1987MalleandDeBeer,1996).
SAAbindstotworeceptors,TLR4andTLR2,whichalsorecognizebacterialPAMPmoleculessuchastriacyl
lipopeptides(incooperationwithTLR1),diacyllipopeptidesorlipoteichoicacids(togetherwithTLR6)
(Schwandneretal.,1999Takeuchietal.,2001,2002Chengetal.,2008Hiratsukaetal.,2008)(Table1).
Recently,Loseretal.showeddirectevidenceforthelocalproductionoftheSAAmoleculesmyeloidrelated
protein8(Mrp8)andMrp14,whichinducedautoreactiveCD8+TcellsandsystemicautoimmunitythroughTLR4
signalinginmice(Loseretal.,2010).Takentogether,thesefindingssuggestthatTLR4maybeakeyreceptorin
thediscriminationoflipidPAMPsfromlipidDAMPsmolecules,becausepromiscuousrecognitionoflipidsvia
TLR4unfortunatelycausesinflammatorydisease.AlthoughaconsensusrecognitionstructureforTLR4hasnotyet
beenidentified,antagonistsofTLR4signalingbylipidDAMPsmightbecandidatedrugsforthetreatmentof
chronicinflammatorydisease.

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SugarrelatedDAMPs Goto:

Hyaluronicacid(HA)isanonsulfatedlinearpolysaccharide,andamajorcomponentoftheextracellularmatrix.
Weigeletal.revealedthatHAisinducedanddegradedduringinflammatoryresponsesandthatitfunctionsin
immunecellactivationornewbloodvesselformation(Weigeletal.,1986).Interestingly,smallmolecularweight
HA(sHA),producedbythedegradationofHAduringinflammation,caninducethematurationofdendriticcells
(DCs)forpathogenelimination(Termeeretal.,2002).BonemarrowderivedDCsfrommiceexpressingnon
functionalTLR4couldnotbeactivatedbysHA,whileDCsfromTLR2deficientmiceretainedtheabilityfor
sHAmediatedactivation.ThissuggeststhatsHAcanactasaDAMPmoleculesignalingthroughTLR4toinduce
DCmaturationuponpathogeninfection(Termeeretal.,2002).Consistentwiththis,excessivesHAlevelsappeared
tobecloselyassociatedwithinflammatoryautoimmunediseasessuchasrheumatoidarthritis,sarcoidosis,systemic
sclerosis,andpancreaticcancer(Hallgrenetal.,1985Witteretal.,1987Sugaharaetal.,2006Yoshizakietal.,
2008)(Table1).

MetaboliterelatedDAMPs Goto:

Uricacid

Uricacidisametaboliteofpurinenucleotidesandfreebasesinhumansandotherprimates,anditfunctionsasan
antioxidanttoprotecterythrocytemembranesfromlipidoxidation(KelloggandFridovich,1977).However,itwas
previouslyshownthatsolubleuricacidinducedinflammatorycytokinessuchasmonocytechemoattractantprotein
1inratvascularsmoothmusclecells(Kanellisetal.,2003).Shietal.alsoreportedthaturicacidisproducedin
ultravioletirradiatedBALB/c3T3cells,andactivatesDCs(Shietal.,2003).Inaddition,highlevelsofuricacidin
thebloodareassociatedwiththedevelopmentofhyperuricemiaandgout(Johnsonetal.,2005),suggestingthatit
actsasaDAMPduringcellinjuryandcaninduceinflammatoryresponsesthatarerelatedtoautoinflammatory
diseasessuchasgout(Table1).

ReceptorsthatrecognizeuricacidhavebeenreportedandLiuBryanetal.revealedthatTLR2,TLR4,andtheir
adaptormoleculeMyD88areimportantforuricacidmediatedinflammation(LiuBryanetal.,2005).Incontrast,
theuricacidmediatedactivationofDCswasshowntobeTLR4independent,suggestingthepossibleexistenceof
otherreceptorsthatrecognizeuricacidinadditiontoTLR2andTLR4(Shietal.,2003).Tosolvethisquestion,
Martinonetal.demonstratedthaturicacidcouldbesensedbyanotherreceptor,NODlikereceptorfamily,pyrin
domaincontaining3(NLRP3),andinducedtoproduceinterleukin(IL)1throughcaspase1activation(Martinon
etal.,2006).NLRP3isamemberoftheNLRfamily,andacomponentoftheinflammasome,aplatformthat
inducesIL1andIL18production.NLRP3sensesvarioustypesofpathogeninfectionsorirritantssuchas
Candidaalbicans,Legionellapneumophila,Listeriamonocytogenes,Malariahemozoin,alum,silica,andasbestos
aswellasuricacid(Kannegantietal.,2006Martinonetal.,2006Dostertetal.,2008,2009Eisenbarthetal.,
2008Grossetal.,2009).Collectively,theseresultsrevealedthatNLRP3isapromiscuousreceptorthatsenses
PAMPsandDAMPsandcaninduceinflammatoryresponses.

Adenosinetriphosphate(ATP)

ATPisanessentialpurinebaserequiredforalmostallphysicalresponsessuchasglucosemetabolism,muscle
contraction,biosynthesis,andmoleculartransfer.However,extracellularATPfrominjuredcellsornonapoptotic
cellsalsoservesasadangersignalthroughtheactivationofNLRP3andcaspase1(Communietal.,2000).
Previousdetailedresearchhasshowntheimportanceofotherionchannelmolecules,namely,P2X7andpannexin
1,ininducingextracellularATPmediatedcaspase1activationfollowingIL1maturation(Ferrarietal.,2006
Kannegantietal.,2007).TheformationoftheNLRP3inflammasomerequiresanadaptormolecule,apoptosis
associatedspecklikeproteincontainingacarboxyterminalcaspaserecruitmentdomain(ASC).ASCdeficient
micecannotactivatecaspase1andthusdonotproducematureIL1followingexposuretolargeamountsofATP,
suggestingthatATPmediatedIL1productionisdependentontheNLRP3inflammasome(Mariathasanetal.,
2004).However,althoughextracellularATPhasbeensuggestedtoactasaDAMPmolecule,thereisnocorrelation
betweenhighamountsofextracellularATPactingasDAMPsinvitroandphysiologicalconditionsinvivo.Eckleet
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al.suggestedthatmostextracellularATPmightbeimmediatelyhydrolyzedbyectonucleotidases(Eckleetal.,
2007).Takentogether,investigationintotherolesofextracellularATPininducingpathologicalandimmune
responsesinvivomayprovideimportantcluesregardingthemechanismunderlyinginflammationinductionby
DAMPmoleculerecognitionorinthedevelopmentofinflammatorydiseases.

NucleicacidrelatedDAMPs Goto:

UnmethylatedCpGmotifandgenomicDNA

Asdescribedabove,uricacidandATPareproductsofpurinemetabolism.Nucleicacidssuchasadenineor
guaninearealsopurinemetabolites.Nucleicacidsexistinallorganismsincludingpathogens,andfunctionasa
storeofgeneticinformationforproteintranslationandsynthesis.BacterialgenomicDNAcanberecognizedasa
PAMP,asitcontainsunmethylatedCpGmotifswhosefrequencyishigheringenomicDNAderivedfrom
pathogenscomparedwiththatofvertebrates.TheearliestresearchrelatedtobacterialgenomicDNAasPAMPs
wasreportedmorethanhundredyearsago.Brunsetal.investigatedheatkilledgramnegativeorgrampositive
bacteriaasanimmunotherapeuticagenttermedColey'stoxin,forcancer(Swain,1895).AlthoughLPSisamajor
factorinmediatingantitumoreffects,otherfactorsmaybeconnectedwithitsphysiologicalfunction,asgram
positivebacteriadonotexpressLPS.AhundredyearsonfromthediscoveryofColey'stoxin,severalstudieshave
shownthatbacterialDNAcanactivatenaturalkiller(NK)cellsorBcells,suggestingthatthebacterialgenomic
DNAinColey'stoxincouldcontributetoitsantitumoractivitybystimulatingNKcells(Shimadaetal.,1986
Messinaetal.,1991).Kriegetal.furtherrevealedthatbacterialgenomicDNAcontainsunmethylatedCpGmotifs
thatcanstimulateBcellsandNKcells,andinduceinflammatorycytokineproduction.Interestingly,methylated
bacterialDNAfailedtostimulateimmunecells,indicatingthatunmethylatedCpGmotifsmayactasPAMP
molecules(Kriegetal.,1995Klinmanetal.,1996).However,whethergenomicDNAcontainingmethylatedCpG
motifsisincapableofinnateimmuneactivationremainscontroversial.In1962,Glasgowetal.reportedthat
ultravioletinactivatedvacciniavirus,aDNAvirus,resultedinIFNproductioninmousecells(GlasgowandHabel,
1962).Inaddition,Suzukietal.showedthatviralDNA,vertebrateDNAandbacterialDNAinducedthe
upregulationofmajorhistocompatibilitycomplex(MHC)classIexpressionandthetypeIIFNrelatedactivationof
transcriptionfactorssuchasSTAT3inratthyroidcells,suggestingthatgenomicDNAalsoactivatesinnateimmune
signalinginaCpGmotifindependentmanner(Suzukietal.,1999).Interestingly,thestructureofDNAstrongly
affectsDNAmediatedinnateimmuneactivation.Doublestranded,righthandedBformDNA,butnottheleft
handedZformDNA,stronglyinducedtypeIIFNproduction.GenomicDNAhasahighcontentofBformDNA,
indicatingthatitmayalsofunctionasaPAMPorDAMP(Ishiietal.,2006).MitochondrialDNAhasbeenalso
reportedtofunctionasaDAMPmolecule.Zhangetal.reportedthatcellularinjurycausedthereleaseof
mitochondrialDNA,andinducedsystemicinflammatoryresponsesviap38MAPKactivationinaTLR9
dependentmanner.Inaddition,traumapatientshadhigheramountsofmitochondrialDNAthandidhealthy
volunteers,suggestingthatmitochondrialDNAcouldbeconsideredamarkerofinflammatorydisease(Zhanget
al.,2010).WhentheclearanceofmitochondrialDNAbyautophagywasinhibited,IL1productionwas
augmentedviatheNLRP3inflammasometoactivatecaspase1,indicatingthattheamountofmitochondrialDNA
DAMPactivityisregulatedbyautophagytosuppresserroneousactivationofinnateimmunity(Nakahiraetal.,
2011).Indeed,itwasrevealedthatautophagynegativelyregulatesRNAmediatedtypeIIFNproduction,possibly
tomaintaincellularhomeostasis(Jounaietal.,2007).

CorrelationbetweenautoimmunediseaseandDNADAMPs

BothDNAandRNAcanfunctionasPAMPsandDAMPs,andarecloselyconnectedwithinflammatoryresponses
andthedevelopmentofinflammatorydisease.DirectevidenceforDNAactingasaDAMPwasshownusing
DNasedeficientmice.DNaseIispresentinextracellularcompartmentssuchastheseraandurine,andfunctionsto
degradesinglestrandedDNA(ssDNA),doublestrandedDNA(dsDNA),orchromatin,whicharereleasedfrom
damagedornecroticcells.Napireietal.constructedDNaseIdeficientmice,andreportedthattheypresentedwith
theclassicalsymptomsofsystemiclupuserythematosus(SLE)andglomerulonephritis(Napireietal.,2000).In
addition,DNaseIIdeficientmiceshowedasimilarphenotypetoDNaseIknockoutmice.DNaseIIinthe
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lysosomesofmacrophagesdegradesDNAfromapoptoticcellsornucleargenomeDNAfromlivererythroblasts.
Interestingly,DNaseIIdeficientmicepresentedwithlethalanemiaowingtohighlevelsoftypeIIFNproduction,
causedbytheaccumulationofnondegradedgenomicDNAinlivermacrophages(Yoshidaetal.,2005).Insupport
ofthis,DNaseIIandIFNRa/bdoubleknockoutmiceshowedanonlethalphenotype,butdevelopedrheumatoid
arthritislikesymptoms(Kawaneetal.,2006),whichcouldbeattenuatedbyantiTNFantibodytreatment.This
suggestedthattheaccumulationofgenomicDNAinmacrophagesinducedinflammatorycytokines,includingtype
IIFNsandTNF,andthesynergisticactionoftheseinflammatorycytokinesresultedinlethalsystemic
inflammation(Kawaneetal.,2006).Furthermore,studiesonDNaseIII,alsoknownasTREX1,alsorevealedthat
DNAcouldfunctionasaDAMP.TREX1isthemajor35DNAexonucleaseforDNAeditinginDNA
replicationorDNArepair.Moritaetal.showedthattrex1deficientmicehadareducedsurvivalrateowingtohigh
susceptibilitytoinflammatorymyocarditis,althoughnullmiceshowednospontaneousmutationsortumor
development(Moritaetal.,2004).Toexplainwhytrex1deficientmicedevelopinflammatorymyocarditis,Crowet
al.demonstratedthatthemutationinthetrex1genethatabolishedTREX1enzymeactivitywasresponsibleforthe
developmentofAicardiGoutieressyndrome(AGS),asevereneurologicalbraindiseasewithhighlevelsofIFN
incerebrospinalfluidorserum,suggestingthatTREX1isasuppressorofDNADAMPmediatedinflammatory
responses(Crowetal.,2006).Furthermore,itwaspreviouslyshownthattheabolishmentofinterferonregulatory
factor3(IRF3)orIFNreceptor1amelioratedtheAGSsymptomsintrex1deficientmice(Stetsonetal.,2008).
Collectively,thesefindingssuggestthatthedysregulationofselfDNAresultsinsevereinflammatoryresponses
suchashighlevelsoftypeIIFNsleadingtoautoinflammatorydisease.

Nucleicacidsensors Goto:

HostcellsareequippedwithnumeroustypesofreceptorstorecognizenucleicacidsasPAMPsorDAMPs.These
receptorsfunctiontoprotectthehostfrompathogeninfection,butmayalsocauseautoimmunedisordersby
inducingtheconstitutiveactivationofinflammatoryresponses(Figure1).Inthissection,weintroducethewell
characterizednucleicacidsensors.

Figure1
Autoimmunedisordersmaybeinducedbypromiscuoussensingof
nucleicacids.

TLRs

AlargebodyofresearchexistsdemonstratingtheTLRmediatedsensingofnucleicacids.TLR3preferentially
sensesdoublestrandedRNA(dsRNA)species,whichcanoriginatefromsomeviruses,andTLR3isassociated
withinductionofinnateimmunityinresponsetoinfectionwithWestNilevirus,respiratorysyncytialvirus,and
encephalomyocarditisvirus(Wangetal.,2004Groskreutzetal.,2006Hardarsonetal.,2007)(Figure2).In
addition,artificialdsRNA,poly(I:C),hasbeenwellcharacterizedasaligandforTLR3.Althoughpathogen
relateddsRNAsactasPAMPs,Karikoetal.reportedthathostmessengerRNAcouldbesensedbyTLR3to
induceinflammatoryresponses(Karikoetal.,2004).RNAreleasedfromnecroticcellscanalsoelicittypeIIFN
production,suggestingthathostRNAmightfunctionasaDAMPuponcellularinjury(Karikoetal.,2004).

Figure2
Intracellularsensorsfornucleicacids.

TLR7andTLR8recognizesinglestrandedRNA(ssRNA),andinduceantiviralinnateimmuneresponsesagainst
influenzavirusorvesicularstomatitisvirus(Lundetal.,2004)(Figure2).Regardlessoftheircommonligands,the
cellularandtissuedistributionofTLR7expressionisincontrasttothatofTLR8.HumanTLR7ishighlyexpressed
inplasmacytoidDCsthatpreferentiallyinducetypeIIFNproduction,andisexpressedatlowerlevelsinmyeloid

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cells.Conversely,thelevelofTLR8expressionishigherinmonocytesandinmonocytederivedDCsthanin
plasmacytoidDCs(Hornungetal.,2002).Furthermore,mouseTLR8didnotrespondtossRNA,buthumanTLR8
did,suggestingthatTLR8mightbeinactivatedinmice,althoughseveralpapershavealsolinkedmouseTLR8
withneuronalapoptosisandautoimmunity(Heiletal.,2004Gordenetal.,2006Maetal.,2006).

InadditiontotherecognitionofPAMPs,Vollmeretal.revealedthatpromiscuousrecognitionthroughTLR7or
TLR8causesthedevelopmentofSLEwithhighlevelsoftypeIIFNsandTNFproduction(Vollmeretal.,
2005).BecausetheserafromSLEpatientscontainshighlevelsofautoantibodiesagainstselfantigens,suchas
smallnuclearribonucleoproteinparticles(snRNPs)includingssRNA,TLR7,orTLR8couldrecognizethe
immunocomplexofsnRNPswithautoantibodiesthoroughFcreceptormediatedinternalization(Vollmeretal.,
2005).Interestingly,TLR7appearstobeaspecificsensorfortheinductionoftypeIIFNproductionfrom
plasmacytoidDCs,whereasTLR8isspecificforTNFproductionfrommonocytesinSLEpatients,suggesting
thatplasmacytoidDCsandmonocytescollaboratetodevelopinflammatoryresponsesinSLEviadistinctsensors.

TLR9sensesssDNAcontainingunmethylatedCpGmotifs.PreviousstudieshaverevealedthatTLR9recognizes
genomicDNAfrompathogenssuchasmurinecytomegalovirusandHerpessimplexvirustype1ortype2as
PAMPs(Hemmietal.,2000Lundetal.,2003Krugetal.,2004a,b)(Figure2).Withregardtothedevelopmentof
autoinflammatorydisease,TLR9hasbeenalsobeenreportedtorecognizeselfantigenscomplexedwith
autoantibodies.Leadbetteretal.revealedthatautoreactiveBcellswereactivatedbyachromatinautoantibody
complexinaTLR9andMyD88dependentmanner(Leadbetteretal.,2002).Inaddition,selfDNAcontaining
immunecomplexes,whichareawellcharacterizedmarkerforSLE,wererecognizedbyTLR9throughFcRIIA
mediatedinternalizationinplasmacytoidDCs(Meansetal.,2005).Thus,immunecomplexescontainingselfDNA
maysignalasDAMPsthroughTLR9,althoughextracellularreceptorssuchasFcRIIAmayberequiredforthe
deliveryofautoimmunecomplexestotheTLR9localizingcompartment.

Asdescribedpreviously,thesubcellularlocalizationofTLRsisimportantfortherecognitionofDNA,because
TLR3,7,8and9localizetotheendosomalcompartment.Previousstudiesidentifiedthreeadaptormolecules,
Unc93B1,PRAT4A,andgp96,whichareimportantforthetraffickingofTLRstositesforsensingtheirligands.
Unc93B1functionstocontrolthetraffickingofTLRs3,7,and9fromtheendoplasmicreticulum(ER)tothe
endosome.PRAT4AislocalizedintheERandactsasaregulatorofthesubcellulardistributionofmostTLRs
exceptforTLR3.Gp96isamemberoftheheatshockprotein(HSP)90family,andresidesintheERwhereit
controlsthematurationofTLRs2,4,5,7,and9(SaitohandMiyake,2009).BecauseTLR7andTLR9are
regulatedbythesamemolecularmachinery,thecrosstalkbetweenTLR7andTLR9mayaffectthesensingofauto
nucleicacidsandthedevelopmentofautoinflammatorydisease.Christensenetal.showedthatadeficiencyof
TLR9resultsinmalignantsymptomsinamousemodeloflupus,despitethelevelsofantibodyproductionspecific
forDNAandchromatinbeingdownregulated(Christensenetal.,2005).Incontrast,TLR7deficientmice
developedattenuatedlupussymptoms(Christensenetal.,2006).Inaddition,arecentstudyrevealedthatTLR9
suppressedtheprogressionofautoinflammatorydiseasebyantagonizingTLR7,suggestingthatTLR9counteracts
TLR7upontherecognitionofselfimmunocomplexescontainingssRNAorssDNA(Nickersonetal.,2010).To
supporttheinteractionbetweenTLR7andTLR9uponthedevelopmentofautoimmunedisease,Fukuietal.
generatedUnc93B1D34A/D34AknockinmicetoshowthatTLR9competeswithTLR7forbindingtoUnc93B1in
thehealthystate,whileTLR7isconstitutivelyactivateduponautoinflammatoryresponsesbecauseTLR9hasa
loweraffinityfortheUnc93B1likeUnc93B1D34A/D34Amutant(Fukuietal.,2011).

RIGIlikereceptors(RLRs)

AlthoughTLRscansensebothnonselfandselfnucleicacids,fibroblasts,andendothelialcellsthatdonotexpress
TLRsalsoproducetypeIIFNsinresponsetoinfectionwithpathogens,indicatingtheexistenceofotherreceptors
thatsensenucleicacids.Yoneyamaetal.determinedthatacytoplasmicDExD/HboxRNAhelicase,RIGI,senses
infectionbyRNAvirusesaswellasartificialdsRNA,andinducesinnateantiviralimmuneresponsesmediatedby
typeIIFNs(Yoneyamaetal.,2004)(Figure2).InadditiontoRIGI,melanomadifferentiationfactor5(MDA5)
andlaboratoryofgeneticsandphysiology2(LGP2)werealsoidentifiedthesereceptorswereclassifiedasRLRs
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becausetheirproteinstructuresweresimilartothatofRIGI(Yoneyamaetal.,2005).Toinduceanantipathogen
immuneresponse,aCARDdomaininRIGIandMDA5transmitsdownstreamsignalsthroughhomophilic
interactionswiththeCARDadaptormolecule,IFNpromoterstimulator1(IPS1,alsoknownasMAVS,Cardif,
orVISA)(Kawaietal.,2005Meylanetal.,2005Sethetal.,2005Xuetal.,2005).ThefunctionofLGP2is
controversial.SomeinvitrostudiesshowedthatLGP2negativelyregulatesRIGIorMDA5mediatedinnate
immuneresponsesbycompetingforbindingwiththeirRNAligands(Yoneyamaetal.,2005Bammingand
Horvath,2009).However,invivostudiesusinglgp2deficientmicerevealedthatLGP2isacofactorofRLR
mediatedinnateimmunesignaling(Venkataramanetal.,2007Satohetal.,2010).

RLRssensepathogenderivedRNAspeciesasPAMPstoinducetypeIIFNproduction,whileMDA5hasbeen
detectedasanautoantigeninclinicallyamyopathicdermatomyositispatients(Satoetal.,2009Nakashimaetal.,
2010).AlthoughitisnotclearhowextracellularMDA5isproduced,theaccumulationofimmunocomplexes
containingMDA5isamarkerforthefrequencyofrapidlyprogressiveinterstitiallungdisease(Satoetal.,2009
Nakashimaetal.,2010).Accompanyingtheseobservations,lossoffunctionsinglenucleotidepolymorphismshave
beenfoundinRIGIandIPS1thatarecloselyrelatedtothedevelopmentofautoimmunedisease(Pothlichetetal.,
2011),suggestingthatinhibitionofRLRsignalingmaybeimportantintheprogressionofautoimmunedisease.
However,asdescribedearlier,excessiveproductionofinflammatorycytokinesincludingtypeIIFNsappearsto
resultinautoinflammatorydisease.Incontrast,thedysfunctionofRLRsinducespoortypeIIFNproduction,but
leadstoautoimmunedisease(Nakashimaetal.,2010Pothlichetetal.,2011).Onepossibilitytoexplainthis
phenomenonisthatnonfunctionalRLRsresultinanincreasedsusceptibilityagainstvarioustypesofvirus
infections,andthesubsequentvirusmediatedcelldeathmaycausethereleaseofDAMPsandsignalingthrough
DAMPreceptors.Supportthispossibility,thelossofMDA5functionincreasedthesusceptibilityofbetacellsto
viralinfectionwithpicornavirusorencephalomyocarditisvirusD,andresultedintype1diabetes,whosetypesof
diabetesareoftencausedbyvirusinfectionorautoimmunity(Collietal.,2010McCartneyetal.,2011).Further
analysesarerequiredtoelucidatethecrosstalkbetweenRLRsignalingandthedevelopmentofautoimmune
disease.

Absentinmelanoma2(AIM2)likereceptors(ALRs)

AlthoughvariousNLRfamilymembersthatcaninducetheactivationofcaspase1andmaturationofIL1,IL18,
andIL33inresponsetoawiderangeofPAMPandDAMPmoleculeshavebeenidentified,nosensorof
intracellulardsDNAforIL1maturationhasbeenidentified.However,fourresearchgroupsconcurrentlyreported
aroleforthenovelintracellularDNAsensor,AIM2,intheactivationofcaspase1followingIL1production
(Burckstummeretal.,2009FernandesAlnemrietal.,2009Hornungetal.,2009Robertsetal.,2009).AIM2
belongstoafamilyofhematopoieticinterferoninduciblenuclearproteinswitha200aminoacidrepeat(HIN200),
knownasthep200orPYHINfamily.Currently,fourHIN200familymoleculeshavebeenidentifiedinhumans,
andsixinmice.HIN200familymoleculessharesimilarstructuralfeatures,includingapyrindomainattheNH2
terminus,andaHIN200domainattheCOOHterminus.SimilartotheroleofNLRP3inIL1production,AIM2
causesoligomerizationoftheinflammasomeuponDNAbinding.TheAIM2inflammasomerecruitsASC,an
essentialadaptormolecule,andinducesNLRP3inflammasomeformationthroughhomophilicinteractionsbetween
thepyrindomaininAIM2andthatinASC(Figure2).TheimportanceoftheAIM2inflammasomeuponPAMP
recognitionhasbeenconfirmedbyinfectionexperimentsusingaim2deficientmacrophagesinfectedwith
Francisellatularensis,L.monocytogenes,vacciniavirus,herpessimplexvirus1andmousecytomegalovirus
(FernandesAlnemrietal.,2010Rathinametal.,2010).

AsecondALR,interferoninducibleprotein16(IFI16)inhumans(ahomologueofp204inmice),hasbeenalso
investigatedasanintracellulardsDNAsensor.However,whileAIM2inducesIL1productioninresponseto
intracellulardsDNAbinding,IFI16isasensorfortypeIIFNproductionuponrecognitionofintracellulardsDNA
(Unterholzneretal.,2010).AlthoughIFI16alsocontainsapyrindomain,thepyrininIFI16isquitedistinctfrom
thatinAIM2asithasaloweraffinityforASC.Consistentwiththesedifferentfeaturesofpyrin,IFI16mediated
typeIIFNproductionuponintracellulardsDNAstimulationwasnotaffectedbyASCdeficiency,suggestingthat
thetwoHIN200familymoleculesregulatebothIL1andtypeIIFNproductionupontherecognitionof
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intracellulardsDNA(Unterholzneretal.,2010).AlthoughAIM2mediatedsignalingappearstobedistinctfrom
IFI16mediatedtypeIIFNproduction,recentresearchhasrevealedthatIFI16negativelyregulatestheAIM2
mediatedactivationofcaspase1(Veerankietal.,2011).Asincreasedinflammatorycytokineproductionisclosely
relatedtothedevelopmentofautoinflammatorydisease,theregulationbetweenAIM2mediatedinnateimmune
signalingandIFI16mightbederegulatedinpatientswithautoimmunedisease.

Robertsetal.identifiedp202andAIM2ascytosolicDNAbindingproteinsinmice.p202isanotherALR
moleculewithoutapyrindomain,indicatinganinabilitytobindASCforinflammasomeformation(Robertsetal.,
2009).p202appearstobeanegativeregulatorforAIM2mediatedsignaling,asthereductionofp202resultsin
higherAIM2mediatedactivationofcaspase1inresponsetointracellularDNA.However,elevatedlevelsofp202
havebeenreportedtoinduceSLElikesymptomsinmice(Rozzoetal.,2001).Interestingly,p202levelsarevaried
amongmousespecies,whileAIM2isexpressedatthesamelevel,indicatingthatp202expressionistightly
correlatedtoSLEdevelopment.Furthermore,Ravichandranetal.revealedthatablationoftheaim2geneleadsto
higherexpressionofp202andtypeIIFNsinmice,andaim2deficientmicearepronetoSLE(Panchanathanetal.,
2010).Takentogether,thesefindingssuggestthatmousep202mightbehomologoustohumanIFI16.Insupportof
this,expressionlevelsofIFI16andantiIFI16autoantibodiesweredramaticallyincreasedinSLEpatients,
indicatingthatIFI16hassimilarfeaturestop202(Mondinietal.,2006).

ArecentarticledescribedacorrelationbetweenpsoriasissymptomsandAIM2activation.Psoriasisisachronic
autoinflammatorydiseasecausedbyincreasedIL1productionleadingtoTh17cellmaturation(Ghoreschietal.,
2010).Dombrowskietal.observedincreasedlevelsofcytosolicDNAfragmentsinskinlesionsfrompsoriatic
patients,whichcouldbesensedbyAIM2(Dombrowskietal.,2011).Interestingly,thoseDNAfragments,which
mightbereleasedfromskinlesionsinpsoriaticpatients,wereinternalizedthroughbindingtotheantimicrobial
peptideLL37(Dombrowskietal.,2011).PreviousstudieshaveshownthatthecomplexofselfDNAwithLL37
canactivateplasmacytoidDCstoproducetypeIIFNs,andcomplexmediatedtypeIIFNproductionisclosely
relatedwithskinlesiondevelopmentinpsoriasis(Nestleetal.,2005Landeetal.,2007).AIM2isaninterferon
induciblegene,suggestingthatLL37complexeswithselfDNAactivateplasmacytoidDCstoproducetypeI
IFNs,andthatthesubsequentupregulationofAIM2leadstoIL1production,andfinally,psoriaticskinlesions
occurbecauseoftheincreasedlevelsoftypeIIFNproductionaswellasIL1production.

Highmobilitygroupbox1(HMGB1)

HMGB1hasbeenreportedtobeamajorDAMPmolecule.Goodwinetal.firstidentifiedHMGB1fromcalf
thymuschromatinasanonhistoneDNAbindingprotein(Goodwinetal.,1973).However,Wangetal.showed
thatamousemacrophagecelllinereleasedHMGB1inresponsetoLPSstimulation.Inaddition,LPStreatedmice
developedincreasedserumlevelsofHMGB1,similartohumanpatientswithsepsis,suggestingthatHMGB1isa
DAMPmoleculeinregardtosepsissymptoms(Wangetal.,1999).Accumulatingevidencesuggeststhatcellular
injuryresultsinthereleaseofHMGB1leadingtoinflammation(Abrahametal.,2000Scaffidietal.,2002).
Consistentwiththeseobservations,numerousstudieshaveshowedacorrelationbetweenHMGB1and
autoimmune/inflammatorydiseasessuchasatherosclerosis,diabetes,SLE,rheumatoidarthritisandSjgren
syndrome(Taniguchietal.,2003Portoetal.,2006Urbonaviciuteetal.,2008Devarajetal.,2009).

Asdescribedpreviously,higherserumlevelsofimmunocomplexesofselfDNAwithautoantibodiesisahallmark
ofSLE.PreviousresearchhasshownthatHMGB1isalsocontainedinimmunocomplexesandcanelicit
inflammatorycytokineproduction,suggestingthatHMGB1maybeacarrierofDNADAMPs(Tianetal.,2007
Urbonaviciuteetal.,2008).Furthermore,HMGB1appearstopromiscuouslybindnumerousmoleculessuchas
LPS,IFN,IL1,andCXCL12toinducesynergisticphysiologicalresponses(Shaetal.,2008Younetal.,2008
Campanaetal.,2009).Moreover,HMGB1cansensepathogenderivednucleicacids,whichinducetypeIIFN
production(Yanaietal.,2009).Collectively,HMGB1mightbeapromiscuouscarrierthatenhancesinnateimmune
responsesagainstPAMPsandDAMPs.

ThereceptorsforHMGB1havebeeninvestigated,butarestillcontroversial.AwellstudiedreceptorforHMGB1
isthereceptorforadvancedglycationendproducts(RAGE).SimilartoHMGB1,RAGEisapromiscuousreceptor
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thatcanbindtovariousligandsincludingDNA,RNA,SAAprotein,HSPsandprionprotein,suggestingthat
RAGEmaysenseavarietyofDAMPmoleculesinanHMGB1dependentorindependentmanner(Simsetal.,
2010).ExperimentswithragedeficientmicerevealedthatHMGB1mediatedDNAsensingrequiresRAGEfor
internalizationofDNAcomplexestoproducetypeIIFNsviaTLR9(Tianetal.,2007).Interestingly,RAGEcould
associatewithTLR9uponrecognitionoftheAtypeofCpGHMGB1complex,indicatingapossiblefunctionfor
RAGEasabridgemoleculebetweentheextracellularHMGB1DNAcomplexandtheTLR9compartment(Tian
etal.,2007).Incontrasttothisobservation,nucleosomescouldsenseHMGB1complexesindependentlyof
RAGE.InsteadofRAGE,TLR2appearstobeimportantfortherecognitionofHMGB1nucleosomecomplexes,
suggestingthatthesensingmachineryoftheHMGB1nucleosomecomplexmightbedistinctfromthatofthe
HMGB1DNAcomplex,astheHMGB1nucleosomecomplexcouldnotelicitproductionoftypeIIFNseven
thoughTNForIL10wereinduced(Urbonaviciuteetal.,2008).Furthermore,recentresearchidentifiedanovel
ligandforRAGE,complementC3a,thatbindshumanstimulatoryCpGDNAtoinducetypeIIFNsinan
HMGB1independentmanner.ThissuggeststhatRAGEmediatedDNAsensingmayinvolvenumerousligands
(Ruanetal.,2010).AlthoughtherearemanyvarietiesofHMGB1orRAGEmediatedDNArecognition,both
moleculesarestronglyassociatedwiththeinductionofinflammationandthedevelopmentofchronicinflammatory
disease.

DNAdependentactivatorofIFNregulatoryfactors(DAI)

DAIhasbeenidentifiedasamoleculethatrecognizesintracellularDNA.PreviousstudieshaverevealedthatDAI
sensesZtypeDNAhowever,itmayalsobindtoBtypeDNAandinducetypeIIFNproductionthrough
associationswithTBK1andIRF3(Takaokaetal.,2007).Interestingly,DAIdeficientmicerespondednormallyto
cytosolicdsDNAstimulation,suggestingthatDAImayfunctionasoneofanumberofDNAsensorsinacelltype
specificfashion(Ishiietal.,2008).Currently,thefunctionofDAIiscontroversial,althoughthegenetic
adjuvanticityofDAIhasbeenshowntoinducestrongcytotoxicTcellresponses(Lladseretal.,2011).Although
theabilityofDAItorecognizeDNADAMPshasnotbeendeterminedyet,DAImightbealinkbetweenthe
developmentofautoimmunediseaseandhostDNAimmunecomplexes.

Histones

HistoneH2B(H2B)isacomponentofchromatin,andKobiyamaetal.identifiedthatH2Balsofunctionstosense
intracellulardsDNA.PreviousreportsshowedthathistonesactasDAMPs,andthatexcessiveintracellulardsDNA
inducestypeIIFNsthroughH2B(Kobiyamaetal.,2010).Inconfirmationofthis,H1orH2arereleasedfromthe
nucleusafterDNAdamage,andaretranslocatedtomitochondriafollowingtheinductionofapoptosis.Inaddition,
H1,H2A,andH2Bmayactasantimicrobialproteinsincertainanimals,suggestingthatH2Bisanintracellular
dsDNAsensorthatrecognizesdsDNAPAMPsandDAMPs(Kawashimaetal.,2011).Histonesmayberelatedto
autoimmunediseasesasantihistoneantibodiesweredetectedinpatientswithsuchdiseases.Furtheranalysesare
requiredtoclarifytherelationshipbetweenhistonesandautoimmunedisease.

Ku70

Ku70functionsinDNArepair,V(D)Jrecombinationandinretainingthetelomere.Zhangetal.showedthat
variousDNAspeciesinducedtheproductionoftypeIIIinterferon,IFN1,andidentifiedKu70asanovelDNA
sensorbypulldownassayfromthenucleuscompartment(Zhangetal.,2011a).WhileotherDNAsensorsare
importantfortheproductionoftypeIIFNs,Ku70appearstobeimportantfortypeIIIIFNproductionthrough
IRF1andIRF7.Furthermore,Ku70mediatedtypeIIIIFNproductionisrestrictedwhenthelengthofintracellular
DNAstimuliisgreaterthan500basepairs.

RNApolymeraseIII

Asdescribedabove,RIGIsensesintracellularRNAspecies,butmayalsorecognizeintracellulardsDNA.siRNA
treatmentofahumanhepatomacellline,Huh7,suppresseddsDNAmediatedtypeIIFNproduction.Subsequently,
Chiuetal.showedthatRIGIsensesthetranscribedRNAbyproductsofDNAtemplatesthataregeneratedby

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RNApolymeraseIII(asisthecaseforpoly(dAdT)poly(dTdA)andEBVgenomicDNA)andinduces
productionoftypeIIFNs(Chiuetal.,2009).AninhibitorofRNApolymeraseIIIsuppressedDNAmediatedtype
IIFNproduction,suggestingthatRNApolymeraseIIIisadistinctDNAsensor.However,RNApolymeraseIII
mediateddsDNAsensingisrestrictedtosequencesofDNAstimulicontaininglessdAdTthandGdC.

DHX9andDHX36

AlthoughtheDExD/HboxRNAhelicasefamilycontainsRIGIandMDA5,whichfunctionasRNAsensors,
recentreportshaverevealedasimilarRNAhelicasefamilyofmolecules(DExDcfamily)thatcontainDHX9and
DHX36,whichfunctionasssDNAsensorsinplasmacytoidDCs(Kimetal.,2010).Interestingly,whileDHX36
sensesCpGA,DHX9sensesCpGBinaMyD88dependentmanner.ThismaysuggestthatssDNAPAMPsor
DAMPsarerecognizedbyeitherDHX9orDHX36,butrecentresearchhasshownthatDHX9collaborateswith
IPS1torecognizedsRNAinmyeloidDCs,indicatingthepromiscuoussensingofDHX9(Zhangetal.,2011b).

Leucinerichrepeatflightlessinteractingprotein1(Lrrfip1)

SomesensormoleculessuchasTLRsorNLRssharecommonmolecularpatterns,suchasleucinerichrepeats
(LRRs),whichareimportantforligandrecognitionorproteinproteininteractions.AnLRRcontainingmolecule,
Lrrfip1,hasbeenreportedtosenseintracellularDNAorRNA(Yangetal.,2010).Interestingly,whereasother
DNAsensorsoftenregulatetypeIIFNrelatedtranscriptionfactorssuchasIRF3/7orcaspase1toinduce
maturationofIL1,Lrrfip1stimulatescateninandCBP/p300toenhanceifnb1transcription,indicatinganovel
pathwayinvolvingcateninfortypeIIFNproductionuponcytosolicDNAsensing.BecauseWnt/catenin
signalingisalsolinkedtotumordevelopment,furtheranalysesmayidentifythemachineryinvolvedinthe
regulationoftypeIIFNsignalingbyLrrfip1undertumordevelopment.

STING(stimulatorofinterferongenesprotein)

ThemajorfunctionofMHCclassIIisantigenpresentation,whilemonoclonalantibodiesagainstMHCclassIIcan
causecellactivationorapoptoticcelldeath.Jinetal.identifiedanoveltetraspaninfamilymolecule,MPYS,
associatedwithMHCIImediatedcelldeath(Jinetal.,2008).ThreeresearchgroupsperformingcDNAlibrary
screeningtoidentifymoleculesassociatedwithactivationofthetypeIIFNpromoteridentifiedthesamemolecule,
STING(alsoknownasMITA,andERIS).STINGisanoveladaptormoleculethatactivatesinnateimmune
signalingmediatedbyintracellularnucleicacidstimuli(IshikawaandBarber,2008Zhongetal.,2008Sunetal.,
2009).Surprisingly,theBarberresearchgroupfurtherrevealedthatSTINGisessentialfortheinductionoftypeI
IFNproductionfollowingsensingofcytosolicdsDNA,usingSTINGdeficientmice.Basedontheirimaging
analysis,STINGappearstolocalizetotheERduringthesteadystate,buttranslocatestotheGolgiapparatusupon
intracellulardsDNAstimulationtoactivatedownstreammoleculessuchasTBK1.ThissuggeststhatSTINGisan
essentialadaptormoleculeforcytosolicdsDNAmediatedtypeIIFNproductioninmice.

CyclicdiGMPandcdiAMParesmallmoleculesthatfunctionassecondmessengersandareimportantforcell
survival,differentiation,colonization,andbiofilmformation.Recentresearchhasrevealedthatthecytosolic
deliveryofcdiGMPorcdiAMPinducedtypeIinterferon(IFN)productionfrombonemarrowmacrophages,
suggestingthatcdiGMPandcdiAMParebacterialPAMPmolecules(McWhirteretal.,2009Woodwardetal.,
2010).AstypeIIFNproductionbycdiGMPorcdiAMPrequirestheirinternalization,liveinvasivebacteria
possiblyproducethesesecondmessengermoleculesafterinternalizationintocells.

RecentreportshaverevealedthatSTINGisadirectsensorofbacterialsecondmessengermolecules,suchascdi
GMPorcdiAMP(Burdetteetal.,2011Jinetal.,2011).ThisindicatesthenovelpossibilitythatcytosolicdsDNA
stimulationmightproducecdiGMP/cdiAMPorrelatedmoleculesthatcanbesensedbySTINGandinducetype
IIFNproduction.

AdjuvanticitythroughDNADAMPs Goto:

AlthoughDNADAMPsarecloselyassociatedwiththedevelopmentofautoimmunedisease,DNADAMPsalso

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contributetotheactivationofacquiredimmuneresponsesfollowingvaccinationwithalumadjuvant.Previous
studieshaveshownthatgenomicDNAfromdyingcellsinducesthematurationofantigenpresentingcellsaswell
asantigenspecificantibodyandcytotoxicTcellresponses.ThissuggeststhatselfDNADAMPscanactivate
innateimmuneresponsesthatinduceacquiredimmunoresponses.Recently,Marichaletal.demonstratedthatthe
adjuvanticityofalumwasdependentonselfDNAreleasedfromcellsatthealuminoculationsite(Marichaletal.,
2011).NLRP3appearstobeakeysensorintheinductionofalummediatedinnateimmunity,althoughitsfunction
isonlypartiallydependentuponalumadjuvanticity.Intraperitonealinoculationofmicewithaluminducedthe
recruitmentofneutrophils,andtheresultingalumdepositscontainedhighamountsofgenomicDNA.Because
treatmentwithDNaseIattenuatedalumadjuvanticity,thealummediatedreleaseofgenomicDNAmayaccountfor
itspotentadjuvanticity.Inaddition,thealummediatedinductionofantibodyproductionisdependentonTBK1and
IRF3asdemonstratedusingknockoutmice,suggestingthatalummediatedgenomicDNAinduceshigh
adjuvanticityofalumviatheTBK1/IRF3pathway,whilealummediateduricacidproductionislessrelatedtoalum
adjuvanticityviaNLRP3(Marichaletal.,2011).Furthermore,selfDNAsfromaluminoculationcanactivate
inflammatorymonocytes,andhomodimersofIL12p40aremoreimportantthantypeIIFNproductionuponalum
adjuvanticity.Takentogether,thesefindingssuggestthatselfDNADAMPsareimportantforpathogenelimination,
thedevelopmentofautoimmunediseaseandtheadjuvanticityofalum.Furtheranalysesarerequiredtoelucidate
whichtypesofcellsproduceselfgenomicDNAafteradjuvantinoculation,andwhichsensorsrecognize
extracellulargenomicDNAs.

Inadditiontoalumadjuvant,therearemanylicensedadjuvantssuchasMF59,AS03,andAS04.Both
MF59andAS03areemulsionsofoil/watercontainingsqualene.Althoughbothadjuvantselicitantibody
responsesaswellascellmediatedimmuneresponsesspecificforantigens,theirmodeofactionhasnotbeen
identified.Informationonthereceptorsforandsignalinginducedbytheseadjuvantsisneeded,becauseunfortunate
sideeffectscanbeexpectedmoreeasily.

Concludingremarks Goto:

Manysortsofnucleicacidspeciesexistintheenvironment.Thesespeciesaffectallorganismssuchastheevolution
oforganisms,theinflammatoryresponse,andtheadventofdrugresistantmicroorganisms.Topreventpathogen
infection,mammaliancellshaveequippedthemselveswithmanysortsofsensorstorecognizeexogenousnucleic
acidspeciesasPAMPs,whilethosesensorsarealsostimulatedbyendogenousnucleicacidsspeciesasDAMPs.
DysfunctionofthemachineriessensingbothPAMPsandDAMPsisstronglyassociatedwithchronicinflammatory
diseaseorautoimmunity.Inaddition,bothPAMPsandDAMPsunderlietheactionofvaccines,becausemost
modernvaccinescontainadjuvants,whicharecomposedofbothPAMPandDAMPassociatedmolecules.
Therefore,themachineryresponsibleforsensingnucleicacidsspeciesshouldbefurtherelucidatedtohelpus
understandmachineryofchronicinfection,autoimmunedevelopment,identifyingthesideeffectsofvaccines,and
developingsafevaccineadjuvants.

Conflictofintereststatement

Theauthorsdeclarethattheresearchwasconductedintheabsenceofanycommercialorfinancialrelationshipsthat
couldbeconstruedasapotentialconflictofinterest.

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