title: microRNA-200b modulates microglia-mediated neuroinflammation via the cJun/MAPK pathway.
abstract: 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.
authors.affiliation: Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Shweta P
authors.initials: SP
authors.lastname: Jadhav
authors.forename: Sandhya P
authors.initials: SP
authors.lastname: Kamath
authors.forename: Mahesh
authors.initials: M
authors.lastname: Choolani
authors.forename: Jia
authors.initials: J
authors.lastname: Lu
authors.forename: S Thameem
authors.initials: ST
authors.lastname: Dheen
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001930:Brain Injuries / Q000473:pathology; D002465:Cell Movement; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D016207:Cytokines / Q000502:physiology; D055785:Gene Knockdown Techniques; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology*; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology*; D017628:Microglia / Q000473:pathology / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D009443:Neuritis / Q000473:pathology*; D009573:Nitrites / Q000378:metabolism; D010766:Phosphorylation; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D000199:Actins; D016207:Cytokines; C555600:MIRN200 microRNA, rat; D035683:MicroRNAs; D009573:Nitrites; D016755:Proto-Oncogene Proteins c-jun; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases
keywords: c-Jun; cJun-N terminal kinase; miRNA-200b; microglia; neuroinflammation