Seite - 121 - in Advances in Neuroimmunology

BrainSci. 2016,6, 23 mousemodel [91,92]. In lymphocytecell linesof JurkatandU937cells,HIV-1 infection-causedparticle production isaccompaniedbyCD44upregulation[93]. InHIV-1-relateddiffuse largeB-cell lymphoma patients, theCD44levelssignificantly increasedcomparedwithHIV-1-unrelateddiffuse largeB-cell lymphomapatients (87%vs. 56%) [94]. ThesefindingssuggestCD44mayplayarole inHIV-1-related remyelinationfailure. Neurotrophins are important factors in the regulation of oligodendrocyte myelination and remyelination. Themain cellular sources for neurotrophins in thebrain are astrocytes,microglial cells, andneurons, in addition to lymphocytes’ contribution through theblood circulation. Being aware of excellent reviews on the alteration of neurotrophins inHAND [95] and immunological communicationsbetweenoligodendrocytesandmicroglia [96],wefocushereontheHIV-1-induced alterationsofneurotrophins thatarepotentiallyassociatedwitholigodendrocyteabnormalities. Theplatelet-derivedgrowthfactor (PDGF) is themostpredominantmitogenforoligodendrocyte lineage cells. PDGFAandBchainsbothpromoteproliferation throughactivatingPDGFreceptor alpha (PDGFRα) expressed onOPCs, whereas the PDGFB chain appears to bemore important for earlyNPC expansion [97,98]. It has been shown that PDGF regulatesOPCdevelopment via glycogen synthase kinase-3β (GSK-3β) signaling pathway, which is a negative regulator ofOPC differentiationandremyelination[99,100]. PDGF-BBpreventsNPCfromTat-mediatedproliferating impairmentby inactivatingGSK-3β/β-cateninpathwaysand, thiseffect is significantly inhibitedby thep38andJNKinhibitors [101]. The levelsoffibroblastgrowthfactor (FGF),which isan important pro-survival signal to stimulate OPC proliferation [102], increased in the sera of HIV-1-infected patients [103,104],butdecreased inCSF[103]. FGFsignalingcomplex is interrupted inHIV-1-infected brains, resulting in theabnormalactivationofdownstreamsignals, includingGSK-3β [105,106],p38, ERK, and JNK cascades [107] in neurons through the surface receptors, such asNMDAreceptor andCXCR4,whicharealsoexpressedonoligodendrocytes [36,108,109]. Inaddition,HIV-1Tatand FGF-2 share a commoncoremechanismofunconventional secretion [110], although it is not clear whether they compete for the secretory routine. The brain-derived neurotrophic factor (BDNF), predominantlyderivedfromastrocytes,hasalsobeenfoundtobeessential foroligodendrocyte lineage development [68,111–113]. In rat primary neurons, gp120 promotes a time-dependent proBDNF accumulation at both intracellular and extracellular spaces by decreasing the expression level of intracellularfurin,anenzymerequiredforcleavageandreleaseofmatureBDNF, leadingtoareduction inmature BDNF.A similar imbalance in the ratio of proBDNF/mature BDNFwas confirmed in postmortembrainsofHANDpatients [114]. Thesefindingssuggest thatHIV-1decreases thebrain BDNFlevelby infectingastrocytesandgp120-associatedneurotoxicity, resulting indownregulated remyelination. AsBDNF is believed to protect neurons fromHIV-1-induced apoptosis, thus, the reduction of BDNF may make the oligodendrocyte lose the support from neuronal axons that consequentlycausemyelindamagethroughthe“inside-out”mechanismasproposed[42]. Inaddition to thesesignalingmolecules,HIV-1Tat interactingprotein (TIP30), aco-factor that specificallyenhancesHIV-1Tat-activated transcription [115], negatively regulatesoligodendrocyte development.OverexpressionofTIP30dramaticallyinhibitstheOPCdifferentiation,whileknockdown ofTIP30 enhances thedifferentiation ofOPC remarkably [116]. The blockadeof TIP30mayhave dual benefits on inhibiting Tat-dependent gene transcription andpromotingOPCdifferentiation, which isapotential therapeuticstrategyforHIV-associateddemyelination. Potassiumchannelsare also involved in regulation ofOPCdevelopment. Kv1.3 [117,118], Kv1.6 [117], Kv2.1 [119], and inward-rectifiedK+ channel 4.1 [120,121]play crucial roles in regulationofOPC/oligodendrocyte proliferation anddifferentiation. Generally, channel expressions onoligodendrocyte lineage cells correlate with differentiating stages and are more complex in OPCs than in oligodendrocytes. Particularly,Kv1.3channelplaysan important role inG1/Stransition inproliferatingOPCsthrough regulatingAKTsignaling[118,122].Moreover,L-typevoltage-operatedCa2+ channel1.2knockdown inducesadecrease in theproportionofoligodendrocytesexpressingmyelinproteins,andanincrease in thepopulationof immatureoligodendrocyte [123]. 121