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brain sciences Article Neuroimmunologyof theInterleukins13and4 SimoneMori 1,PamelaMaher2 andBrunoConti 1,* 1 DepartmentofChemicalPhysiology,TheScrippsResearchInstitute,10550NorthTorreyPinesRoad, LaJolla,CA92037,USA;smori@scripps.edu 2 CellularNeurobiologyLaboratory,SalkResearchInstitute,La Jolla,CA92037,USA;pmaher@salk.edu * Correspondence: bconti@scripps.edu;Tel.:+1-858-784-9069 AcademicEditor:DonnaGruol Received: 26April2016;Accepted: 2 June2016;Published: 13 June2016 Abstract:Thecytokinesinterleukin13and4shareacommonheterodimericreceptorandareimportant modulatorsofperipheralallergic reactions. ProducedprimarilybyT-helper type2 lymphocytes, they are typicallyconsideredasanti-inflammatorycytokinesbecause theycandownregulate thesynthesis ofT-helpertype1pro-inflammatorycytokines. Theirpresenceandroleinthebrainisonlybeginningto beinvestigatedandthedatacollectedsofarshowsthat thesemoleculescanbeproducedbymicroglial cellsandpossiblybyneurons.Attentionhassofarbeengiventothepossibleroleof thesemolecules in neurodegeneration. Bothneuroprotectiveorneurotoxiceffectshavebeenproposedbasedonevidence that interleukin13and4canreduce inflammationbypromoting theM2microgliaphenotypeand contributingto thedeathofmicrogliaM1phenotype,orbypotentiatingtheeffectsofoxidativestress onneuronsduringneuro-inflammation. Remarkably, theheterodimeric subunit IL-13Rα1of their commonreceptorwasrecentlydemonstratedindopaminergicneuronsof theventral tegmentalarea and the substantianigrapars compacta, suggesting thepossibility that both cytokinesmayaffect theactivityof theseneurons regulatingreward,mood, andmotor coordination. Inmiceandman, thegene encoding for IL-13Rα1 is expressedon theX chromosomewithin thePARK12 regionof susceptibility toParkinson’sdisease (PD).This, togetherwithfindingthat IL-13Rα1contributes to lossofdopaminergicneuronsduring inflammation, indicates thepossibility that thesecytokinesmay contribute to theetiologyor theprogressionofPD. Keywords: Interleukin13; Interleukin4;neuron;microglia; Parkinson;brain; neurodegeneration; neuroinflammation;neurotoxic;neuroprotection 1. Introduction In this reviewwesummarize thecurrentbodyofknowledgeon the roleof IL-13 in thecentral nervous system.Although the studyof this subject is in its infancy andonly a limited amount of workhasbeendoneat thisstage, it is likely that thiswill change inthenear future. In fact,oneof the interestingaspectsof investigating thebiologyof IL-13 in the centralnervous system(CNS) is that its canonical receptor, alphatypeI (IL-13Rα1), appears tobeexpressednotonly inglial cellsduring pathologicalconditions,butalsoinspecificsubsetsofneuronsinthehealthybrain. Specifically,IL-13Rα1 has, so far, been foundondopaminergicneuronsof theSubstantiaNigrapars compacta (SNc) and theVentralTegmentalArea(VTA)[1]. This findingindicates that its ligands, IL-13andIL-4,couldbe importantregulatorsofdopaminergic functionandcell survival,andmayprovideadirect linkbetween the immunesystemandtheneurobiologyofreward,addiction,ormotorcoordination. 2.WhatWeKnowaboutIL-13ComesfromStudiesofItsBiologyintheImmuneSystem Thecytokines Interleukin13 (IL-13)andinterleukin-4 (IL-4)are twosecretedproteinsrecognized for their role inpromotingT-helper type 2 (Th2) lymphocyte-mediatedallergic inflammationand BrainSci. 2016,6, 18 43 www.mdpi.com/journal/brainsci