Page - 54 - in Advances in Neuroimmunology

BrainSci. 2016,6, 41 microglial functionand this combinedwith theSN’s reduced resilience to reactiveoxygenspecies (ROS)couldpromoteneurodegeneration. The role of neuroinflammation in PD is also particularly important in the context of aging. Inflammation isknownto increasewithage. This is largelyattributedto theagerelatedchanges in microglialphysiology.Microglia,myeloidderivedmacrophages,are theresident immunecellof the CNSandconstitute 10%of the cell population. Their highly ramifiedprocesses arehighlymotile andconstantly surveyparenchyma, facilitating thedetectionandthecellular response to infection andinjury.However,microgliaarealso involvedinmanyhomeostatic functionsandarenowknown tobehighlyactiveduringpost-natal synapticpruningandsynapticplasticity [17,18].Microgliaare known to undergo a phenomenon known as primingwith age. This describes a propensity for microglia toattainapro-inflammatorystateandischaracterizedby4principal features: (1)primed microgliawill exhibithigher levelsof inflammatorymediatorsandsurfacemakerseven in theabsence of immune stimulation; (2)microglia alsodemonstrate hyperactivity upon subsequent activation where theyreleaseexaggeratedamountsofcytokinesandreactiveoxygen/nitrogenspecies; (3) they arealsoresistant toregulatorymechanismsthat typicallyrestoremicrogliabackto their inactivated state, causing themto remain in anaggravated state for a longerperiodof time [19]; and (4) they donot respond to stimuli, suchas IL4, thatpromote anti-inflammatory factors, angiogenesis, and neurotrophic factorsecretion [19,20]. Forexample,Lee,Ruizetal. (2013) inducedmicroglialactivation in thebrainsofyoungandoldmicewith theapplicationofacytokinecocktaildesignedtoelicitanM1, pro-inflammatoryphenotype (IL1β+ IL12) or ananti-inflammatory,M2phenotype (IL-4+ IL-13). TheseauthorsdemonstratedthatM1cocktail elicitsan increasedresponsemicroglia fromtheaged brain,while thesameagedcellswere less responsive to theM2cocktail. Thisphenomenonhasbeen reproducedwith isolatedmicrogliaandhasbeentermedpriming[21]. Inorder to elucidate themolecularunderpinningsof the age-relatedalterations inmicroglial function,numerousresearchershavebeguntoassess thedifferentialexpressionofgenesandprotein inprimarymicroglia.ArecentstudyusingRNAseqcomparingthe transcriptionalprofilesof isolated microglia towholebrainhas identifiedthemicroglial sensome[22]. Theseauthors furtherassessed the sensome inmicroglia isolated from aged animals and demonstrated thatmany of the genes relatedtosensingendogenous ligandsweredownregulated,whereasgenespertainingtohostdefense wereup-regulated. Furthermore,anotherrecentstudyusinggenemicroarraysof isolatedmicroglia identified an up-regulation of NFκB related genes in these aged cells [23]. Sustained microglial activationandmicroglialprimingcanperpetuateneurodegenerationby increasingcellular stressboth fromenhancedreleaseofcytotoxicsubstances,butalso fromthe lossof trophicsupportasaresultof impairedmicroglialhomeostatic function. 3.RoleofNeuroinflammation The precise pathophysiology that precipitates the development of PD is unknown, although it is understood that a few key biological processes are often impacted in patients, includingmitochondrial function, proteostaisis, immune function leading to oxidative stress and inflammation. Neuroinflammation is critical factor in the disease process that clearly contributes significantly to theneurodegenerationseeninPD.However, it isdifficult toascertain if inflammation initiatespathological featuresofPD,or is triggeredbythewidespreadproteinaggregationandneuronal deaththatoccursduringdiseaseprogression.McGeeretal. (1988)describedthepresenceof increased reactive gliosis and infiltrating T-cells around the SN in post mortem analysis of PD brains [24]. Theirobservationsprovidedsomeofthefirst indicationsthat increasedneuroinflammationisassociated withDAcelldeath.Manyotherstudieshavereportedfeaturesof inflammationinpost-mortemsamples, suchasincreasedlevelsofinflammatorymediatorslikeiNosandCox-2[25],supportingthecontribution of increasedneuroinflammationduringadvancedstagesof thedisease. Similarpatternsofactivated microgliahavebeendetectedinthebrainareasassociatedwithclinical symptomsof thedisease[26]. Interestingly, this distribution of gliosiswas evident in both newlydiagnosedpatients and those 54