microRNA-200b modulates microglia-mediated neuroinflammation via the cJun/MAPK pathway
Article first published online: 9 MAY 2014
© 2014 International Society for Neurochemistry
Journal of Neurochemistry
Volume 130, Issue 3, pages 388–401, August 2014
How to Cite
J. Neurochem. (2014) 130, 388–401.
- Issue published online: 18 JUL 2014
- Article first published online: 9 MAY 2014
- Accepted manuscript online: 3 APR 2014 02:43AM EST
- Manuscript Accepted: 1 APR 2014
- Manuscript Revised: 11 MAR 2014
- Manuscript Received: 14 DEC 2013
- ASTAR-MINDEF-NUS. Grant Numbers: 09/1/50/19/621, R-181-000-141-305
- NMRC Exploratory/Developmental Grant. Grant Numbers: 1039/2011, R-181-000-139-275
- cJun-N terminal kinase;
Chronic activation of microglia, the macrophages of the CNS, has been shown to enhance neuronal damage because of excessive release of proinflammatory cytokines and neurotoxic molecules in a number of neurodegenerative diseases. Recent reports showed altered microRNA (miRNA) expression in immune-mediated pathologies, thus suggesting that miRNAs modulate expression of genes involving immune responses. This study demonstrates that miRNA-200b is expressed in microglia and modulates inflammatory response of microglia by regulating mitogen-activated protein kinase pathway. miRNA-200b expression was found to be down-regulated in activated microglia in vivo (traumatic brain injury rat model) and in vitro. A luciferase assay and loss- and gain-of-function studies revealed c-Jun, the transcription factor of cJun-N terminal kinase (JNK) mitogen-activated protein kinase pathway to be the target of miR-200b. Knockdown of miR-200b in microglia increased JNK activity along with an increase in pro-inflammatory cytokines, inducible nitric oxide synthase expression and nitric oxide (NO) production. Conversely, over-expression of miRNA-200b in microglia resulted in a decrease in JNK activity, inducible nitric oxide synthase expression, NO production and migratory potential of activated microglia. Furthermore, miR-200b inhibition resulted in increased neuronal apoptosis after treatment of neuronal cells with conditioned medium obtained from microglial culture. Taken together, these results indicate that miRNA-200b modulates microglial inflammatory process including cytokine secretion, NO production, migration and neuronal survival.
Chronic microglial activation is implicated in the pathogenesis of several neurodegenerative diseases. Recently, miRNAs, the novel epigenetic factors, have been shown to be involved in several diseases including neurological disorders. In this study, we demonstrate that miR-200b is expressed in microglia and modulates inflammatory response of activated microglia by altering the expression of proinflammatory cytokines, NO production and neuronal survival via targeting the cJun MAPK pathway. Thus, miRNA-200b may prove to be a useful therapeutic target in the context of chronic neuroinflammation.