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PMID: 22363497 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

MicroRNA 146a (miR-146a) is over-expressed during prion disease and modulates the innate immune response and the microglial activation state.

PloS one ·Vol. 7 ·No. 2 ·2012-00-00 ·Pages e30832

Saba R, Gushue S, Huzarewich RL, Manguiat K, Medina S, Robertson C, Booth SA

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.

MeSH Terms
Animals Brain/drug effects,metabolism,pathology Cell Line Cell Movement/drug effects Cluster Analysis Cytokines/pharmacology Gene Expression Profiling Immunity, Innate/drug effects,genetics Inflammation Mediators/metabolism Kinetics Lipopolysaccharides/pharmacology Mice MicroRNAs/genetics,metabolism Microglia/drug effects,immunology Oxidative Phosphorylation/drug effects Prion Diseases/genetics,immunology Prions/metabolism Protein Biosynthesis/drug effects Signal Transduction/drug effects Time Factors Toll-Like Receptor 2/antagonists & inhibitors,genetics,metabolism Toll-Like Receptor 4/antagonists & inhibitors,metabolism Transcription, Genetic/drug effects Up-Regulation/drug effects,genetics
Chemicals
Cytokines Inflammation Mediators Lipopolysaccharides MicroRNAs Mirn146 microRNA, mouse Prions Tlr2 protein, mouse Tlr4 protein, mouse Toll-Like Receptor 2 Toll-Like Receptor 4
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Saba Reuben
Molecular PathoBiology, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada.
Gushue Shantel
Huzarewich Rhiannon L C H
Manguiat Kathy
Medina Sarah
Robertson Catherine
Booth Stephanie A
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Article Info
Journal
PloS one
Abbr.
PLoS One
ISSN
1932-6203
DOI
10.1371/journal.pone.0030832
Published
2012-00-00
Epub
2012-00-17
Pages
e30832
Language
English
Region
United States
NLM ID
101285081
PMCID
PMC3281888
Subset
IM
External Links
PubMed source DOI: 10.1371/journal.pone.0030832 PMC Full Text View journal details
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