Page - 133 - in Advances in Neuroimmunology

BrainSci. 2017,7, 11 Similarly, theneuroinflammatoryresponseappears toplayamajor role inboth theearlyandchronic deficienciesobservedfollowingTBI. 3.MechanismsofNeuropathologyFollowingTBI It isnowwidelyacknowledgedthatTBI isacomplexmultimodaldiseaseprocess,notasingle pathophysiological event [62]. It causes structural and functional damage,which lead to deficits resultingfrombothprimaryandsecondary injurymechanisms[63]. Theprimary injury is theresult of the immediatemechanical damage fromdirect contact and/or inertial forces to the brain that occursat themomentof the traumatic impact. Thisdamagecan includedirectneuronal, glial and othercellulardamage, contusion,damagetobloodvessels (hemorrhage)andaxonal shearing[64,65]. Secondary injuryevolvesoverminutes, todays, tomonths, toyearsafter theprimary injuryandis the result of cascades ofmetabolic, cellular andmolecular events. Theseoccur concurrentlywith, andcontribute to,alterationsofendogenousneurochemical, inflammatoryandneuroinflammatory mechanisms. Suchmechanismsultimately leadtobraincelldeathorrescue,plasticity, tissuedamage andatrophy[35,66,67].Manybiochemicalalterationsresponsible forsecondary injuryhavealsobeen identified. These include, perturbation of cellular calciumhomeostasis, glutamate excitotoxicity, mitochondrial dysfunction, increased free radical generation, inflammation, neuroinflammation, increased lipidperoxidation,apoptosisanddiffuseaxonal injury (DAI) [68]. Interestingly,allof these alterationscanbe linkedeitherdirectlyor indirectly toneuroinflammation,andsuchinflammationhas been implicated in theearlyandchroniccomponentsofTBI-inducedneuropathology[69–71]. 4. InflammationFollowingTBI:AnImmunologicalPerspective 4.1. Innate,Non-Specific ImmuneResponse toTBI Atpresent, theprevailingviewpoint intheTBIfieldhasbeenthatmost, ifnotallof theinflammation that followsaTBI canbe considered components of the innate immune response [72–74]. However, accumulatingevidenceusingupdatedtechnologysuggests thatspecificadaptiveimmunemechanisms arealsoatplay.Thus,aworkingoperationaldefinitionisneededtodefine immunespecificityafterTBI, andfewauthorshaveadequatelyseparatedinnatefromadaptiveimmunecomponentsafteraTBI.The earlyneuroinflammatoryresponseacross injuriesandinjurymodelsoccurs inarelativelystereotypical mannerandcanlargelybeconsideredtoconsistmainlyof innate immunemechanisms.Whendamage tothebraintakesplaceduringTBI, it triggers thereleaseandproductionofcytokinesandchemokines, whichactivatereceptors,andresults in localandsystemic immuneresponses[72,75,76]. Theneteffect of these innate inflammatorymediators is aimedat limiting the spreadof the injuryandrestoring homeostaticbalance [77]. 4.2. Cytokines inTBI Cytokinesarecategorizedbystructuralandfunctionalcomponents, canbeeitherpro-and/or anti-inflammatory and, in a classical immunological sense, aremediators of the cellular immune response,aswellasofantibodysynthesisandrelease.Cytokinescanbesynthesizedand/orreleasedby awidevarietyofcells, includingmicroglia,macrophages,TandBlymphocytes, endothelialandmast cells [78,79].AlthoughafulldiscussionofcytokinechangesandfunctionsafterTBI isbeyondthescope of this review,several reports indicate that interleukin (IL) IL1-β, IL18andtumornecrosis factoralpha (TNFα)are involvedin theonsetanddevelopmentof the inflammatorycascadeafterTBI inrodents andhumans [72–74]. IL1-βbinds to IL1-receptors, primarily localizedonmicrogliaandastrocytes in thebrain, but also to other cell types, including infiltrating immune cells [80,81]. Activationof theneuroglial and immunecell IL1-receptors initiates theproductionandreleaseof inflammatory cytokines, including increasedproductionof IL1-βandIL18[82]. This results inaself-perpetuating, pro-inflammatory environment, which may be damaging to the CNS parenchyma [75,76,83,84]. 133