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BrainSci. 2017,7, 11 Thedamagingeffectsof IL1-βcanalsoberelatedtoactivationofotherpro-inflammatorypathways, suchas,TNFα [85]andIL18[72]. Several studiessupport theevidenceof rapidandsustained inductionofTNFα indamagedbrain tissue,withinonehourafterTBI inrodentmodels [75,76,86]. TNFα triggers theproductionofother cytokines (IL1-β, IL6), chemokines [75]andnuclear factorkappaB(NF-κB) family (p50,p52andp65) of transcriptionfactors. Thus,TNFα isan importantmodulatorof inflammation,at the transcriptional andtranslational levels, in thenervoussystemandinnon-neural tissues [87,88]. IL18alsoappears to playanimportant inflammatoryroleafterTBI. IL18hasbeenshowntobeelevatedfollowinganumber ofCNSinflammatory insults [89–91], includingTBI [72]. Inhumansandrodents, the IL18pathway cancontribute todelayedneuronal injury,upto14days followingTBI [72].Activatedneuroglialand immunecells in theareaof injurysecrete IL18,whichbinds to the IL18receptor.Activationof the IL18 receptor initiates inflammatorysignalingcascades [92]. Thus, cytokines, someofwhichhavebeen mentionedhere,aremajorcontributors to the inflammatoryandneuroinflammatoryresponse. 4.3. Chemokines inTBI Chemokines (CCL) are chemotactic inflammatory proteins that mediate interactions among inflammatorycellsandtargetcells. Ingeneral, chemokinesare typically10KDaorsmaller.CCLsare synthesizedand/orreleasedalongwithothermediatormoleculesbyavarietyofcell types that include: astrocytes,microglia,macrophages, eosinophils, neutrophils, dendritic cells,mast cells andnatural killercells (NKcells) [93–95]. Releaseofchemokinesserves tochemotacticallyguidereceptor-sensitive cells,primarilythroughactivationofGprotein-coupledreceptors [96]. Similar tocytokines,chemokines can be either pro- and/or anti-inflammatory. After a TBI, chemokines contribute to the attraction of awide range of immune cells to the site of damage [97,98]. The specific activities of classes of chemokineshavebeenelucidatedfollowingTBIs [99–101].Althoughafulldiscussion isbeyondthe scopeof this review,oneexample,CXCchemokines,activates themigrationofneutrophils to thesiteof the lesion[96].Alternatively, chemokinesCCL2,CCL3,CCL5,CCL7,CCL8,CCL13,CCL17andCCL22 attractmonocytesandmacrophages [102–104].Otherchemokines, suchas,CCL1,CCL2,CCL17and CCL22,are involvedin therecruitmentofT-lymphocytes [103]. Anotherimportantroleofcytokineandchemokinereleaseis toactivatepatternrecognitionreceptors (PRRs). PRRs are proteins of the innate immune system and identify danger-associatedmolecular patterns(DAMPs)ofcellularstress. This identification,andtheensuingresponse,helpsdefendagainst celland/or tissuedamage[105,106]. ThePRRsaredividedintoseveral subgroups,dependingoncell localization, typeandfunction.Onesuchgroupisthenucleotide-bindingdomainleucine-richrepeats (NLRs)[107],whicharealsocalledthenucleotideoligomerizationdomain(NOD)-likereceptors. These receptorsare locatedinthecytoplasmandhelptoregulate thehost inflammatory,apoptoticandinnate immuneresponses[108,109]. TheNLRfamilyofproteinscanbeactivatedbymultiple typesofcell/tissue damagethatareseeninTBIandcanformmulti-proteincomplexescalled“inflammasomes”[110]. The uniquecompositionsof these inflammasomesdependontheextentandtypeofcellandtissuedamage. SomereportssuggestedthespecificcontributionsofNLRfamilyproteins(NLRP3-inflammasome)after TBI[110,111]. TheNLRP3-inflammasomehasbeendetected inneurons,astrocytesandmicroglia in thecortexafterTBI [110],andtheNLRP3-inflammasomecomplex isassociatedwith increases in the aforementionedIL1-βandIL18[108,110,112]. Interestingly, theNLRP3-inflammasomehasalsobeen demonstrated toassociatewithotherCNS inflammatorydisorders, includingAlzheimer’sdisease (AD)[113],which isan increasedrisk factor followingTBI. Thus, theoverall contributionsof thecytokinesandchemokinesreleasedafterTBIaremediated bytherelease,andsubsequent recruitmentof immunecells to thesiteof injury,andtocoordinate the ensuingactivityof thesecells. These immunecellsareanessentialpartof the innate immuneresponse andalso theputative transitionto theadaptive immuneresponseandwillbediscussedbelow. 134