title: MicroRNA 146a (miR-146a) is over-expressed during prion disease and modulates the innate immune response and the microglial activation state.
abstract: Increasing evidence supports the involvement of microRNAs (miRNAs) in inflammatory and immune processes in prion neuropathogenesis. MiRNAs are small, non-coding RNA molecules which are emerging as key regulators of numerous cellular processes. We established miR-146a over-expression in prion-infected mouse brain tissues concurrent with the onset of prion deposition and appearance of activated microglia. Expression profiling of a variety of central nervous system derived cell-lines revealed that miR-146a is preferentially expressed in cells of microglial lineage. Prominent up-regulation of miR-146a was evident in the microglial cell lines BV-2 following TLR2 or TLR4 activation and also EOC 13.31 via TLR2 that reached a maximum 24-48 hours post-stimulation, concomitant with the return to basal levels of transcription of induced cytokines. Gain- and loss-of-function studies with miR-146a revealed a substantial deregulation of inflammatory response pathways in response to TLR2 stimulation. Significant transcriptional alterations in response to miR-146a perturbation included downstream mediators of the pro-inflammatory transcription factor, nuclear factor-kappa B (NF-κB) and the JAK-STAT signaling pathway. Microarray analysis also predicts a role for miR-146a regulation of morphological changes in microglial activation states as well as phagocytic mediators of the oxidative burst such as CYBA and NOS3. Based on our results, we propose a role for miR-146a as a potent modulator of microglial function by regulating the activation state during prion induced neurodegeneration.
authors.affiliation: Molecular PathoBiology, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada.
authors.forename: Reuben
authors.initials: R
authors.lastname: Saba
authors.forename: Shantel
authors.initials: S
authors.lastname: Gushue
authors.forename: Rhiannon L C H
authors.initials: RL
authors.lastname: Huzarewich
authors.forename: Kathy
authors.initials: K
authors.lastname: Manguiat
authors.forename: Sarah
authors.initials: S
authors.lastname: Medina
authors.forename: Catherine
authors.initials: C
authors.lastname: Robertson
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Booth
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D016000:Cluster Analysis; D016207:Cytokines / Q000494:pharmacology; D020869:Gene Expression Profiling; D007113:Immunity, Innate / Q000187:drug effects / Q000235:genetics*; D018836:Inflammation Mediators / Q000378:metabolism; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D017628:Microglia / Q000187:drug effects / Q000276:immunology*; D010085:Oxidative Phosphorylation / Q000187:drug effects; D017096:Prion Diseases / Q000235:genetics* / Q000276:immunology*; D011328:Prions / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D051195:Toll-Like Receptor 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D035683:MicroRNAs; C534190:Mirn146 microRNA, mouse; D011328:Prions; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4