Page - 46 - in Advances in Neuroimmunology

BrainSci. 2016,6, 18 Sexdifferencecanplayarole inaffectingtheroleof IL-13 in theMSmodel.Whileautoimmune diseases, includingMS,aremorecommoninwomen[76], the incidenceandseverityofEAEinmice, null for IL-13,was lower infemalescomparedtomales, suggestingthepossibility that thecontribution of IL-13toEAE/MSmaybegenderspecific[77]. Tothisend, it is interestingtonote that theexpression of IL-13mRNAcanbedecreasedbyestrogen inamousemodelof inflammatory intestinedisease [78] andthat thegeneencodingfor IL-13Rα1 is locatedontheXchromosomeinbothhumansandmice. Together, thesestudiessuggest that IL-13mayhaveaneuroprotectiverole inMS.Althoughthis may be different in other neurodegenerative diseases that, unlike MS, are not characterized by aseverely-compromisedblood-brainbarrier,andarenotprimarilymediatedbyperipheral immune cells, IL-13 and IL-4 also showed protection in a mouse model of Alzheimer’s disease (AD). Specifically, intracerebral injectionof amixtureof IL-13and IL-4 reducedamyloiddepositionand improvedspatial learningandmemory inanADtransgenicmousemodelwhenapplied toyoung micebutdidnotshowprotectiveeffectswhenadministered inadultanimals [79]. 6. Parkinson’sDisease TheIL-13systemmayhaveaspecificroleinthepathogenesisand/ortheprogressionofParkinson’s disease (PD).Dataminingusing theOnlineMendelian Inheritance inMan (OMIM)database [80] showed that IL-13Rα1 lies within the PARK12 region of susceptibility to PD. Although PARK12 comprisesa largeportionofDNA, it is locatedontheXchromosome,anobservationthatmaybeof interest in thatPDhasahigher incidence inmenthaninwomen.Evenmore intriguingwasthe finding thatexpressionof IL-13Rα1 in thebrainappeared tobespecific to thedopaminergicneuronsof the VTAandof theSNc, the regionaffectedbyPD.Double-immunostaining studies also revealed that approximately80%of theSNcneuronsexpressingthedopaminergicmarker tyrosinehydroxylasealso expressedIL-13Rα1[1]. Thepossiblecontributionof IL-13Rα1 toneuronal fatewasmeasuredusingapro-inflammatory experimentalmousemodelofPD.Animals receivedperiodicperipheral intraperitoneal injectionsof bacterialLPSoveraperiodofsixmonths,a regimenpreviouslydemonstratedto inducecentral loss ofdopaminergicSNcneurons [81]. Comparativeanalysis showedthatmice lackingIL-13Rα1were protectedfromneuronal losswhencomparedto theirwild-type littermates, suggestinganeurotoxic actionof its ligands, IL-13and/or IL-4. Invitroexperimentsusingadopaminergiccell lineshowed, however, thatneither IL-13nor IL-4hadcytotoxiceffectswhenadministeredalone.However,both cytokines increasedthe toxicityofnon-toxicdosesofoxidants inadose-dependentmanner. Thus, activation of IL-13Rα1 may be one of the mechanisms whereby the vulnerability of dopaminergicneurons is increasedduring inflammation,whenbothcytokinesandROSareproduced. On the other hand, the lack of neurotoxicity of IL-13 or IL-4 in the absence of ROS suggests that thesecytokinesmaybecapableof regulatingneuronal functionbyaffecting theneurobiologyof those neurons thatparticipate inreward,addiction,andmotorcontrol. Investigating thesephenomena is likely toprovide important informationonthemechanismsof howIL-13andIL-4and,moregenerally, the immunesystem,maybecapableof influencingbehavior orcancontribute toneurodegeneration. 7.Conclusions Although in its infancy, the investigationof thecentral roleof the interleukins13and4has is anexcitingareaof research.Whatmakes it soattractive is that these twocytokinescanbeproduced locally in theCNSandareactiveonbothmicrogliaandneuronalcells.Ofspecial interest is the fact that theyact throughacommonheterodimeric receptor that isexpressed indopaminergicneurons. Althoughthese twoTh2cytokinesareconsideredanti-inflammatory, studiesconductedsofarshow that theycanhavecytotoxiceffectsonbothgliaandneurons. Interestingly theseactionsarenotdue to an intrinsic toxicityof IL-13andIL-4but rather to theirability to increase thecellular susceptibility to oxidativestress. Thissuggest thatunderpathological conditions, suchasneuroinflammationwhen 46