MicroRNA 146a (miR-146a) Is Over-Expressed during Prion Disease and Modulates the Innate Immune Response and the Microglial Activation State 英文参考文献.docVIP

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MicroRNA 146a (miR-146a) Is Over-Expressed during Prion Disease and Modulates the Innate Immune Response and the Microglial Activation State 英文参考文献.doc

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MicroRNA 146a (miR-146a) Is Over-Expressed during Prion Disease and Modulates the Innate Immune Response and the Microglial Activation State 英文参考文献

MicroRNA146a(miR-146a)IsOver-Expressedduring PrionDiseaseandModulatestheInnateImmune ResponseandtheMicroglialActivationState ReubenSaba1,2.,ShantelGushue1,2.,RhiannonL.C.H.Huzarewich1,KathyManguiat1,SarahMedina1, CatherineRobertson1,StephanieA.Booth1,2* 1MolecularPathoBiology,NationalMicrobiologyLaboratory,PublicHealthAgencyofCanada,Winnipeg,Manitoba,Canada,2DepartmentofMedicalMicrobiologyand InfectiousDiseases,UniversityofManitoba,Winnipeg,Manitoba,Canada Abstract Increasing evidence supports the involvement of microRNAs (miRNAs) in inflammatory and immune processes in prion neuropathogenesis.MiRNAsaresmall,non-codingRNAmoleculeswhichareemergingaskeyregulatorsofnumerouscellular processes.WeestablishedmiR-146aover-expressioninprion-infectedmousebraintissuesconcurrentwiththeonsetofprion depositionandappearanceofactivatedmicroglia.Expressionprofilingofavarietyofcentralnervoussystemderivedcell-lines revealedthatmiR-146ais preferentiallyexpressedincellsofmicrogliallineage.Prominentup-regulation ofmiR-146awas evidentinthemicroglialcelllinesBV-2followingTLR2orTLR4activationandalsoEOC13.31viaTLR2thatreachedamaximum 24–48hourspost-stimulation,concomitantwiththereturntobasallevelsoftranscriptionofinducedcytokines.Gain-andloss- of-functionstudieswithmiR-146arevealedasubstantialderegulationofinflammatoryresponsepathwaysinresponsetoTLR2 stimulation.SignificanttranscriptionalalterationsinresponsetomiR-146aperturbationincludeddownstreammediatorsof thepro-inflammatorytranscriptionfactor,nuclearfactor-kappaB(NF-kB)andtheJAK-STATsignalingpathway.Microarray analysis also predicts a role for miR-146a regulation of morphological changes in microglial activation states as well as phagocyticmediatorsoftheoxidativeburstsuchasCYBAandNOS3.Basedonourresults,weproposearoleformiR-146aasa potentmodulatorofmicroglialfunctionbyregulatingtheactivationstateduringprioninducedneurodegeneration. Citation: Saba R, Gushue S, Huzarewich RLCH, Manguiat K, Medina S, et al. (2012) MicroRNA 146a (miR