Page - 45 - in Advances in Neuroimmunology

BrainSci. 2016,6, 18 ROSproductionhasbeenrecentlyshowninalternatively-activatedmonocytes/macrophages through activationofmonoaminooxydaseA(MAO-A) [44]. 3. ExpressionofIL-13andIL-4 intheCNS Asmentionedabove, IL-13andIL-4weredemonstrated tobeproducedperipherally. Todate, there isnoevidence that these twoproteins,bothwithmolecularweights in therangeof15kDa,can cross theblood-brainbarrier.However,experimentalworkshows, instead, their localproduction in theCNS.Expressionof IL-13 in the rodentbrainwasdescribed inmicroglia,where itsproduction wasenhancedbyperipheral injectionofLPSor theneurotoxin1-metil-4-fenil-1,2,3,6-tetraidropiridina (MPTP) [47–51]. EvidencealsoexiststhatbothIL-13andIL-4canbeproducedbyneuronalcellsofthehippocampus and the cortex in experimentalmodels of ischemic insult [52,53]. In this context it has speculated that theproductionof IL-4andIL-13, inducingalternativeactivationofmicroglia—knownas theM2 state—canexertaprotectiveeffectagainstneuronaldamage[53–55].Neuronalproductionof IL-4has beendescribed lately in thenoradrenergicneuronsof the locuscoeruleus, inwhich its releaseappears tobesensitive tobehavioral stress [56]. Preliminarywork inour laboratoryalsoshowedthat IL-13can beproducedinneurons [57]. 4.WhatIs theRoleofIL-13andIL-4 intheCNS? Fewstudieshave testedtheeffectsof IL-13andIL-4 in theCNS.Mostof thesehave investigated apossibleactiononneuronal survivalwithsomestudiesfinding that IL-13and/or IL-4potentiate theeffectsofLPSandInterferongamma(IFN-y), increasingoxidativedamageandcontributing to neuronaldeath [47–50,58–61].Ontheotherhand,otherstudies indicatedthat IL-13and/or IL-4could beneuroprotectiveeitherbydirectlyreducinginflammationorbyinducingthedeathofmicrogliacells thatareconsideredtobecellularmediatorsofneuronaldamage[47–50,59–65].Notably,both IL-13 andIL-4canpotentiateLPS-inducedsicknessbehaviorwhenco-injectedcentrallywithLPS,whereas only IL-4,andnot IL-13,attenuatesLPS-inducedsicknessbehaviorwhenadministeredseveralhours beforeLPS[47,66]. Recently,our laboratorycollectedevidence that IL-13andIL-4arenot toxicwhen administeredalonebut cangreatly increase the susceptibilityofneurons tooxidativedamageand contribute to theirdemise if theyexpress IL-13Rα1 [1]. 5. IL-13andIL-4 inMultipleSclerosis Multiplesclerosis (MS) isanautoimmunedisorderaffectingtheCNSwitharelapsing-remitting timecourse. IL-13seemstoexertaprotectiveroleinthiscontext,asit isbelievedthatinthedevelopment ofthedisease,acrucialroleisplayedbytheimbalancebetweenpro-inflammatorycytokines(IL-1β;TNF; INF-γ; IL-17)andanti-inflammatorycytokines(IL-4, IL-5, IL-10andIL-13)[67,68]. IL-13polymorphisms areassociatedwithautoimmunediseasesandalso increasesusceptibility toMS[69]. AstudyinhumanswithMSfoundthathighlevelsof IL-13inthecerebralspinalfluid(CSF)might exert aneuroprotectiveeffectbyenhancingGammaAminobuthirricAcid (GABA)overglutamate transmission [64]. Interestingly, an earlier report describes IL-4 having the same neural effect of increasing theGABA-induced inward current in neurons in a dose-dependent and reversible manner [70]. Moreover, the copolymerglatiramer acetate, an immunomodulatorydrug currently used to treatMS, has shown to significantly increase theTH2- lymphocyteproductionof IL-13 in patients [71]. Consistently, using the mouse experimental model of MS, experimental autoimmune encephalomyelitis (EAE),Cashandcolleaguesshowedthat IL-13exerts itsanti-inflammatoryaction by inactivatingmacrophagesandreducingoxidative stress [72]. In the samemodel, an increase in circulatingandspleenIL-13preventedaxonal injury [73]aloneor insynergywithIL-4 [74],whereas IL-13reductionwasassociatedwith lossofprotection[75]. 45