NF-κB A Double-Edged Sword Controlling Inflammation 2022 Danhui Liu.pdf

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biomedicines
Review
NF-B:ADouble-EdgedSwordControllingInflammation
DanhuiLiu1,ZhenyuZhong1,*andMichaelKarin2,*
1DepartmentofImmunology,UniversityofTexasSouthwesternMedicalCenter,Dallas,TX75390,USA;
danhui.******@
2LaboratoryofGeneRegulationandSignalTransduction,DepartmentofPharmacology,
UniversityofCaliforniaSanDiego,LaJolla,CA92093,USA
*Correspondence:zhenyu.******@(.);karinoffl******@(.)
Abstract:Inflammation,whenproperlymountedandpreciselycalibrated,isabeneflcialprocess
thatenablestherapidremovalofinvadingpathogensand/orcellularcorpsesandpromotestissue
repair/
transcriptionfactor,thenuclearfactor-kappaB(NF-B)transcriptionfactorfamilyplaysacentralrole
inamplifyinginflammationbyinducingtheexpressionofinflammatorycytokinesandchemokines.
Additionally,NF-Balsoinducestheexpressionofpro-survivaland-proliferativegenesresponsible
,recentstudieshavesuggestedthatthe
NF-Bpathwaycanalsoexertinhibitoryeffectsonpro-inflammatorycytokineproductiontotemper
,wereviewourcurrentunderstandingaboutthepro-andanti-inflammatory
rolesofNF-Banddiscusstheimplicationofitsdichotomousinflammation-modulatingactivityin
thecontextofinflammasomeactivationandtumorigenesis.
Keywords:NF-B;inflammation;NLRP3inflammasome;mitochondrialdamage;mitochondrial
DNA;mitophagy;cancer
Citation:Liu,D.;Zhong,Z.;Karin,M.
NF-B:ADouble-EdgedSword

Biomedicines2022,10,
/,a
biomedicines10061250rapidlymountedinflammatoryresponseiscriticalforneutralizing/eliminatingpathogens
AcademicEditors:VeroniqueBaudand/orcellularcorpses[1].However,oncethisgoalisachieved,theinflammatoryflame
andAmedeoAmedeineedstobeextinguishedpromptlytoinitiatetissuerepairandregeneration,whichul-
timatelyrestoreshomeostasisandorganismalhealth[2].Whenthehostfailstoresolve
Received:30March2022inflammation,asevidencedbyprolonged,uncontrolledimmuneactivationevenafterthe
Accepted:23May2022clearanceofinsults,itoftenresultsinanimpedimentoftissuerepair,leadingtotheloss
Published:27May2022ofnormaltissuefunctionandtheconsequentdevelopmentofchronicsyndromessuch
Publisher’sNote:MDPIstaysneutralasautoinflammatory/autoimmunediseases,degenerativeormetabolicdisorders,and
withregardtojurisdictionalclaimsinvarioustypesofcancer[2].Therefore,awell-balancedandpreciselycontrolledinflamma-
publishedmapsandinstitutionalaffll-toryresponseiscrucialforinsultclearanceandtissuerepair,whileavoidingdevastating
—ultimatelyrestoringhomeostasis[1,3–5].
Inflammatoryresponsesareinitiateduponhostrecognitionofinflammatorycuesin
theformofeitherpathogen-derivedmolecules(PAMPs)orself-dangersignalsgenerated
duringtissuedamage(DAMPs),bydiversepatternrecognitionreceptors(PRR)[5,6].
Copyright:©-likereceptorfamilypyrindomaincontaining3(NLRP3)isaPRRthatactsasa
LicenseeMDPI,Basel,Switzerland.
dominantinnateimmunesensorfortissuedamage,andthusplaysanindispensablerole
Thisarticleisanopenaccessarticle
inignitingsterileinflammation[1,7].Bysensingself-dangersignals,NLRP3undergoes
distributedunderthetermsand
conditionsoftheCreativeCommonsaconformationalchangethatresultsinunfoldingandbindingtotheadaptorprotein
Attribution(CCBY)license(https://ASCthroughhomotypicpyrin–pyrindomaininteractions,ultimatelyleadingtoASC
-caspase-1toeventuallyform
/).alargecytosolicproteincomplextermedtheNLRP3inflammasome,whoseoutcomeis
Biomedicines2022,10,:///biomedicines10061250:.
Biomedicines2022,10,12502of13
self-cleavageandautoactivationofpro-caspase-1,generatingmaturecaspase-
caspase-1thenprocessespro-IL-1andpro-IL-18intotheirbioactiveforms,respectively,
toinitiateinflammation[6].NLRP3inflammasomeactivationiscrucialformounting
protectiveimmunityinresponsetoinjurybystimulatingpunchydamageclearanceand
tissuerepairpathways[8].However,aberrantNLRP3inflammasomeactivationhasalso
beenshowntodrivetheprogressionofmanymajorhumandiseases,includingvarious
typesofcancer,aswellasmetabolicanddegenerativedisorders[9–11].
Nuclearfactor-B(NF-B)wasflrstdiscoveredin1986byDavidBaltimore’sgroupas
atranscriptionfactorinvolvedinB-celldevelopmentandactivation[12–14].Subsequent
studiesestablishedabroadroleofthistranscriptionfactorindiversecellularprocesses,
includinginflammation,cellproliferationandsurvival,differentiationofeffectorand
regulatoryTcells,
rapidresponsetranscriptionfactor,NF-Bfamilymembersareretainedinthecytoplasm
inaninactivestateinrestingcellsbybindingtotheinhibitorofNF-B(IB)[13].Upon
stimulationbyPAMPs,DAMPs,orproinflammatorycytokines,theengagementofPRR
andcytokinereceptorstriggersdownstreamsignalingcascades,leadingtotheactivation
oftheIBkinase(IKK)
degradationoftheIBstoliberateNF-Bdimersfornucleartranslocation,resultingin
theexpressionofpro-survivaland-proliferativegenes,aswellasvariouscytokinesand

inflammationisnolongerneeded,IKKisdeactivatedandIBsaccumulateandremove
NF-BdimersfromtheDNAbacktothecytoplasm[15,16].
Asaresultofitskeyroleininitiatinganinflammatoryresponse,NF-Bwasthought
tobean“ideal”drugtargetforthetreatmentofdiverseinflammatorydiseases[17].How-
ever,quiteunexpectedly,thepharmacologicorgeneticinhibitionofNF-Bwasfound
toexacerbate,ratherthanattenuate,inflammationinmanypreclinicaldiseasemodels,
-
tionofseveraldrug-developmentprogramstargetingIKKorothercomponentsofthe
NF-Bpathway[1,3,17,18].Itwasnotclearuntilrecentlythattheseseeminglycounter-
intuitiveresultscanatleastpartiallybeexplainedbythefactthatNF-Balsoactsasa
macrophage-,we
summarizerecentadvancementsinunderstandingthepro-andanti-inflammatoryproper-
tiesofNF-Banddiscussitsimplicationininflammasomeactivationandtumorigenesis.
-BSignalingPathway
TheNF-BfamilytranscriptionfactorsconsistofflvedifferentDNAbindingproteins
thatshareaRelhomologyregion(cRel,RelA,RelB,NF-B1,andNF-B2)andcanform
upto15homodimersandheterodimers[19,20].Inrestingcells,thesedimersarekeptin
thecytoplasminaninactiveformthroughbindingtoIBproteinsthatmasktheirnuclear
localizationsequence(NLS).
TherearetwodistinctNF-Bsignalingpathwaysoperatinginthecell:canonical

responsetostimulationwithPAMPs/DAMPs(.,LPS,polyI:C,andCpGDNA)andproin-
flammatorycytokines(.,TNFandIL-1),oruponT-andB-cellreceptorengagement[21].
AlthoughtheupstreamsignalingeventsvaryamongdifferentNF-Bactivatingrecep-
tors,thedownstreamsignalingconvergesontheIKKcomplexcomprisedofthecatalytic
subunitsIKK/andtheregulatorysubunitIKK
/,theIKKcom-
plexphosphorylatesIBmoleculesontwoadjacentserineresidues,therebypromoting
K48-linkedubiquitinationtoinducetheproteasomaldegradationofI-
Bdimersthentranslocateintothenucleuswheretheyinitiatethetranscriptionofalarge
setofgenes[13],includingpro-inflammatorycytokinesandpro-survivalmolecules,aswell
asenzymesthatgeneratenon-proteininflammatorymediators,soastoamplifyinflamma-
toryresponsesand/orpromotecellproliferationandsurvival[14].Givenitsindispensable
rolesinregulatingmultiplecellularfunctions,theNF-Bpathwayneedstobetightly:.
Biomedicines2022,10,12503of13
,the
NF-,whichencodesIB,
isoneoftheNF-BtargetgenesthatservesasaninhibitorbybindingtotheNF-Bdimer,
therebyterminatingtheNF-,deubiquitylation
alsonegativelyregulatesNF-,CYLD(cylindromatosis),adeubiq-
uitinase,wasshowntonegativelyregulatethecanonicalNF-Bpathwaybydisassembling
K63-ubiquitinchainsonTRAF2,TRAF6,andNEMO,therebyinhibitingIKKactivation[22].
ThealternativeNF-Bpathwayplaysanessentialroleininducinggenesassociated
withsecondarylymphoidorgandevelopmentandmaintenance[14].However,incontrast
totherapidlyinducedcanonicalNF-Bpathway,activationofthealternativepathway
requiresdenovosynthesisofNF-B-inducingkinase(NIK,alsoknownasMAP3K14),and
,includinglymphotoxin(LT),recep-
toractivatorofNF-Bligand(RANKL;alsoknownasTNFSF11),CD40ligand(CD40L),
andB-cellactivatingfactoroftheTNFfamily(BAFF;alsoknownasTNFSF13B),serveas
theligandsforthealternativeNF-Bpathway[23–25],which,throughactivatingIKK
homodimers,drivetheNF-B2/p52-RELBdimeractivation[25,26].
-andAnti-InflammatoryPropertiesofNF-B
NF-Bistraditionallyviewedasakeytranscriptionalactivatorofanarsenalofpro-
inflammatory,-survival,and-proliferativemolecules[17].Consistentwiththisnotion,itis
well-documentedthatmostofthepro-inflammatorycytokine/chemokinegenespossess
NF-B-bindingsite(s)intheirpromoter/enhancerregions,andtheactivationofNF-Bis
essentialfortheirinductioninresponsetoalargearrayofimmunostimulatorystimuli[27].
Moreover,overactivationofNF-Bsignalingisevidentinmanychronicinflammatory
disorders,suchasinflammatoryboweldisease(IBD)[28,29],rheumatoidarthritis(RA)[30],
andpsoriasis,amongothers[28,30–33](Table1).TheabilityofNF-BtoinduceTNF
,all
ofthesedisordershaverespondedtoanti-TNFtherapyandNF-Binhibitors[34–40].In
acuteinflammatoryconditionssuchassepsis,geneticpolymorphismspotentiatingNF-B
activationhavebeenfoundtoincreasemortalitybecauseofexcessiveinflammation[41,42].
Together,theseflndingsimplythattargetingNF-Bsignalingmightbebeneflcialfortreating
inflammatorydiseases[17].However,contradictingthisnotion,pharmacologicalorgenetic
inhibitionofNF-Bhasbeenshowntoexacerbate,ratherthanattenuate,inflammationun-
dervariousdiseasesettings[3,18],leadingtotheterminationofseveraldrugdevelopment
pipelinesaimingtoinhibitIKK-drivenNF-Bactivationtoeliminateinflammation.
Thisunexpectedanti-inflammatorypropertyofNF-Bcanbebothindirectand
direct[1,3,17].Theformeroftentakesplaceatbarriersurfaces(.,skinandintestine),
whereNF-B-mediatedpro-survivalsignalingensuresproperbarrierfunctiontoprevent
microbialtranslocation[29,43,44].Inadditiontoclassicalpro-survivalmolecules,including
BCL-XL,FLICE-likeinhibitoryprotein(FLIP),andmembersoftheinhibitorofapoptosis
(IAP)family[16],theexpressionofothermoleculesinvolvedinthepreservationofepithelial
integrityisalsounderthecontrolofNF-B[29].Inlinewiththisconcept,thelossofIKK
inintestinalepithelialcells(IECs)drasticallyincreasessusceptibilitytochemical-induced
colitisinmice[43].Similarly,micelackingIKK
/NEMOinIECsdisplayasevereand
spontaneousinflammatorycondition[44],andtheabsenceofIKK
inmousekeratinocytes
canalsoleadtothedevelopmentofapsoriasis-likeinflammatorydisease[29].Incontrast
totheseindirecteffects,thedirectanti-inflammatoryfunctionofNF-Bislargelyattributed
toitsabilitytolimittheproductionofakeyproinflammatorycytokine—IL-1.Thiswas
flrstdemonstratedinourearlierstudyinwhichpharmacologicorgeneticinhibitionof
NF-BunexpectedlyexacerbatedIL-1-dependentinflammationinvivo[18].Micelacking
Ikkexpressioninmyeloidcellsweremoresusceptibletolipopolysaccharide(LPS)-or
bacteria-