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

Reuben Saba,Shantel Gushue,Sarah Medina,Stephanie A Booth,Catherine Robertson,Rhiannon L C H Huzarewich,Kathy Manguiat,Corinne Ida Lasmezas

doi:10.1371/journal.pone.0030832

Reuben Saba, Shantel Gushue + Show 6 more

Open Access

https://doi.org/10.1371/journal.pone.0030832

Copy DOI

Journal: PloS one	Publication Date: Feb 17, 2012
Citations: 141	License type: CC BY 4.0

Affiliation: Public Health Agency of Canada, University of Manitoba

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.

Highlights

Prion diseases, or Transmissible Spongiform Encephalopathies (TSEs), belong to a group of progressive neurodegenerative conditions that affect the nervous system in humans and animals
The microglial cell-line enriched cluster contained 20 miRNAs including miR-146a and a number of other miRNAs reportedly involved in inflammation, such as miR-155, miR-221 [23] and miR-147, a microRNA that is induced upon Toll-like receptor (TLR) stimulation and regulates murine macrophage inflammatory responses [24]
Microglial cells, the brain’s resident immune effector cells, respond to prion deposition by the conversion of a resting phenotype into one that is ‘activated’. They take on an activated phenotype they synthesize fairly low levels of pro-inflammatory cytokines; presumably as a defense mechanism to prevent the severe pathology that can arise in host tissue as a result of an acute inflammatory response induced by rampant signaling in phagocytes

Summary

Introduction

Transmissible Spongiform Encephalopathies (TSEs), belong to a group of progressive neurodegenerative conditions that affect the nervous system in humans and animals. They can have a genetic etiology as well as occurring sporadically without any known risk factors or gene mutations. As is the case in other neurodegenerative conditions, such as Alzheimer’s disease, one of the pathological features of disease is the activation of the brain’s resident immune cells, the microglia, and the accumulation of astrocytes In many instances, this feature can be detected prior to clinical symptoms and other signs of neurodegeneration, such as spongiosis and neuronal cell death become apparent [2,3]

Methods

Results

Conclusion