title: MicroRNA-181c negatively regulates the inflammatory response in oxygen-glucose-deprived microglia by targeting Toll-like receptor 4.
abstract: Cerebral hypoxia/ischemia rapidly induces inflammation in the brain, which is characterized by microglial activation and the release of inflammatory cytokines. We have previously demonstrated that miR-181c can directly regulate tumor necrosis factor (TNF)-α production post-transcriptionally. Here, we determined that hypoxia up-regulated TLR4 expression but down-regulated miR-181c expression in primary microglia. We also demonstrated that miR-181c suppresses TLR4 by directly binding its 3'-untranslated region. In addition, miR-181c inhibited NF-κB activation and the downstream production of proinflammatory mediators, such as TNF-α, IL-1β, and iNOS. Knocking down TLR4 in microglia significantly decreased TLR4 expression and inhibited NF-κB activation and the downstream production of proinflammatory mediators, whereas ectopic TLR4 expression significantly abrogated the suppressed inflammatory response induced by miR-181c. Therefore, our study identified an important role for the miR-181c-TLR4 pathway in hypoxic microglial activation and neuroinflammation. This pathway could represent a potential therapeutic target for cerebral hypoxic diseases associated with microglial activation and the inflammatory response. Cerebral hypoxia/ischemia induces microglial activation and the release of inflammatory cytokines. We found that hypoxia down-regulated miR-181c in primary microglia. In addition, miR-181c inhibited TLR4 expression through binding to its 3'UTR, thus inhibiting NF-kB activation and the production of downstream proinflammatory mediators. Therefore, the miR-181c-TLR4 pathway may be a potential therapeutic target for the treatment of cerebral hypoxic diseases.
authors.affiliation: Department of Neurology, Huadong Hospital, Fudan University, Shanghai, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Ya-Jian
authors.initials: YJ
authors.lastname: Li
authors.forename: Xun-Yi
authors.initials: XY
authors.lastname: Wu
authors.forename: Zhen
authors.initials: Z
authors.lastname: Hong
authors.forename: Wen-Shi
authors.initials: WS
authors.lastname: Wei
mesh_terms: D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology; D002478:Cells, Cultured; D005260:Female; D053263:Gene Regulatory Networks / Q000502:physiology; D005947:Glucose / Q000172:deficiency*; D018836:Inflammation Mediators / Q000378:metabolism*; D035683:MicroRNAs / Q000378:metabolism*; D017628:Microglia / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D018836:Inflammation Mediators; C540193:MIrn181 microRNA, human; D035683:MicroRNAs; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D005947:Glucose; D010100:Oxygen
keywords: TLR4; hypoxia; miR-181c; microglial activation; neuroin-flammation