Seite - 34 - in Advances in Neuroimmunology

BrainSci. 2016,6, 6 5.TNF-αandHypoxia TNF-α, apro-inflammatorycytokineproducedprimarilybymonocytesandmacrophages in the peripheryandmicrogliaandneurons in theCNS, is involvedinthepromotionof the inflammatory responseandcognitivedysfunction [64,65]. TNF-α is initiallyproducedasa212-aminoacid-longtype II transmembranethat is stableasahomotrimer. Thecleavageof themembrane-integratedformby TNF-α convertingenzymeproducesa solublehomotrimer,whichbinds toeitherof tworeceptors, TNFreceptor type1 (TNFR1)orTNFreceptor type2 (TNFR2). TNFR1 is constitutively expressed throughoutmost tissues and is thought to be themainTNF signaling receptor. The activation of TNF-R1 leads toeitherapoptoticcelldeathor theactivationofeither thecaspase-8pathwayorc-Jun NH2-terminalkinase (JNK)pathways, orneuroprotection through thebindingof IκBkinase (IKK) complexandthesubsequentactivationof theNFκBpathway[66]. Thesignalingnetwork inTNF-R1 is interestingdueto theextensivecrosstalkbetweentheNFκB,andJNKsignalingpathways. Thecells susceptibility to apoptosis increases in the absenceofNFκB.TheactivationofTNFR2 leads to the activationof theNFκBpathway,phosphatidyl-inositol-3kinase (PI3K)andsubsequent transcriptionof neuroprotectivemediators likecalbindinandmanganesesuperoxidedismutase [67,68]. Specifically in microgliaactivationofTNFR2anti-inflammatorypathwaysmaybe induced[69].Aputativerole for TNF-αhasbeenshowninrats infusedwith lipopolysaccharide (LPSmaypromote thesecretionof pro-inflammatorycytokines includingTNF-αandIL-1β) into thefourthventricle to inducechronic neuroinflammation [70]. TNF-α synthesis inhibitionwas foundto restore theneuronal functionas wellas reversecognitivedeficits inducedbythechronicneuroinflammation[70]. It isbecomingapparent thatTNF-α isoneof themost important inflammatorycytokines tobe studied inrelation toneuronaldamagecausedbytheabsenceofoxygendueto the fact that it actively participates in the immune-mediatedinflammationofstrokeandotherneurodegenerativediseases withanhypoxia component [71]. The releaseofTNF-α is a result of thepathogenesisofdisorders suchasstroke [72],Alzheimer’sdisease [73],Parkinson’sdisease [74]andsevere infectionssuchas meningitis [75],yet its roleduringhypoxia isnot fullyunderstood. Insevere ischemiaTNF-α levels appeartobeelevatedinaffectedbraintissueafter24h[76].Onesuchcriticalrole inneuroinflammation hasbeenillustratedwherebyTNF-αcandamagedopaminergicneuronsandthusanti-TNFagentsmay ameliorateParkinson’sdisease [74].Despitemanyresearchpapers in thisfieldfewlaboratorieshave investigatedtheeffectsofacutehypoxiaandinflammatorymediatorsonsynaptic transmission[77,78]. Recentlyour laboratoryreportedthat recoveryofsynaptic transmission inCA1neuronswas impaired post-hypoxia in thepresenceofTNF-α [77]. It alsobeenshownthatHIF-1αhasabindingsite for the FasAssociatedDeathDomainpromoter,which isanadaptermolecule inTNFR1mediatedcelldeath. Therefore ithasadirect role inTNF-αmediatedapoptosiswhichmayhelpexplain thepoorrecovery ofEPSPs followingahypoxic insult [79]. Agrowingbodyofevidence indicates thatTNF-αmayplayarole in theregulationof tolerance to chronichypoxiasuchasoccurs in ischemiayet ithasadeleteriouseffect in ischemicbrain injuryafter stroke[80]. Itseemsthatadministrationofahighdoseof lipopolysaccharide(LPS)mayinducearobust inflammatoryresponse thatcanresult in lethal septicshockwhereasadministrationofa lowdoseof LPSmayinduceaprotectivestateof tolerancetosubsequentexposuretoLPSatdoses thatmightcause serious injury [81,82]. In factLPSpreconditioning isknowntoexertneuroprotection fromcerebral ischemia[83,84]. IncerebellargranuleneuronstheneuroprotectiveeffectsofLPSpreconditioningwere said tobe independentofendogenous IL-1βbutdependentonendogenousTNF-αandalso IL-6 [85]. Our laboratorieshaverecentlyprovidedevidence thatTNF-αhasapreconditioningeffect following aglutamate toxic insult24h later in theCA1regionofratorganotypicslices [65].Wesuggestedthat thepreconditioningeffectsmaybeasaresultofchangingrestingCa2+ levelsandCa2+ influxinthe presenceofTNF-α. 34