Page - 2 - in Advances in Neuroimmunology

BrainSci. 2016,6, 19 CNSglial cellsarecapableofproducingavarietyofproinflammatorycytokinesandchemokines, butthespecificbiologicalactionsandrolesoftheseneuroimmunefactorshaveyettobefullyelucidated, andarelikelytodependonthecellsourceandphysiologicalorpathologicalcontext.Duringconditions associatedwithCNSdisease and injury,multiple neuroimmune factors are commonly, andoften chronicallyproduced. The complexity of this situationmakes it difficult to identify the actionsof specificneuroimmunefactorsandthecell source,especially ifpharmacological,biological,orother typesof toolsare lacking.Anumberofapproacheshavebeenusedtocircumvent thisproblem.This article focusesononeapproach, theuseof transgenicmice thatendogenouslyproduceelevated levels ofaspecificneuroimmunefactor in theCNSbyacell type thatnormallyproduces it, andwithin the anatomical integrityandphysiologicalpathwaysof theCNS.Thetransgenicmiceof interest in this reviewexpresselevatedlevelsof theproinflammatorycytokineInterleukin-6 (IL-6), thechemokine CCL2(CCchemokine ligand2,previouslyknownasmonocytechemoattractantprotein-1orMCP-1), or the chemokineCXCL10 (previously knownas interferon-gamma inducible protein 10 or IP10) throughincreasedastrocyteexpression. Thereviewsummarizesstudiesontheconsequencesof the increased astrocyte expression on a basicmechanismofCNS function, synaptic function, and in particular, hippocampal synaptic function. Thehippocampusplays a critical role in learning and memory, and alterations in hippocampal synaptic function can significantly affect cognition [13]. Studies inexperimentalmodelshaveshownthatalteredhippocampalsynaptic function isassociated withCNSconditionsknownto involveelevatedexpressionofneuroimmune factors (e.g., [14–26]). Thetransgenicmicehavealsobeenausefulmodel foranumberofother typesofstudiesrelatedto CNSconditionsduringdiseaseandinjury,a topic that isnotaddressed in this review(e.g., [27–34]). 2.AstrocytesAreaPrimarySourceofNeuroimmuneFactors in theCNS Astrocytesare themostabundantcell type in theCNSandakeycomponentof theneuroimmune systemoftheCNS[35].AstrocytesplayavarietyofrolesintheCNS,asregulators/mediatorsofnormal physiologyandresponders toadverseconditions, suchas thoseoccurringduring injuryandinfection, whenastrocytes contribute to repair and recoveryprocesses [36,37]. A largenumber of cytokines and chemokines are produced by astrocytes, including IL-6, CCL2, and CXCL10, but relatively little is knownabout the specific roles andbiological actions of these factors under physiological orpathophysiological conditionswhenastrocytesare the initial cell sourceof these factors.Astrocytes are in close associationwith neurons and synapses,making them ideally positioned to influence neuronalcircuitactivity,which isessential fornormalCNSfunctionandisoftencompromised inCNS disorders [38,39]. In this review, studieson the consequenceof elevatedastrocyte expression IL-6, CCL2,orCXCL10onsynaptic functionat theSchaffercollateral toCA1pyramidalneuronsynapseof thehippocampusaresummarized. TheSchaffercollateral toCA1pyramidalneuronsynapse isoneof themosthighlystudiedsynapse in theCNS[40]. Output fromtheCA1regionprovides important input tootherbrainregionsandplaysakeyrole in learning,memory,andothercognitive functions. 3. SignalTransductionPathways IL-6,CCL2andCXCL10initiatebiologicalactions throughtheactivationofspecificmembrane receptors, IL-6R,CCR2,andCXCR3,respectively.However,downstreamsignal transductionpathways differ.CCR2andCXCR3areG-proteincoupledreceptors(GPCRs),whereasIL-6Rislinkedtoatyrosine kinasesignal transductionpathway(Figure1).Moreover, IL-6Rassociatedsignal transductioncan occur throughtwopathways,aclassicpathwayandtrans-signaling[41] (Figure1). The classic IL-6 pathway involves membrane bound IL-6R, which interacts with another membrane bound protein, gp130, the signaling subunit of IL-6R and other cytokine receptors. Trans-signaling involves IL-6R that has been released from cells into the extracellular fluid and is referredtoassoluble IL-6R.Soluble IL-6Rcanbindto IL-6 in theextracellularfluidandthe ligand/ receptorcomplexcanthenbindtomembraneboundgp130. Becausegp130 isubiquitouslyexpressed inCNS cells, trans-signaling can occur in cells that do not expressmembrane bound IL-6R, and 2