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.
Keywords: TLR4; hypoxia; miR-181c; microglial activation; neuroin-flammation.
© 2014 International Society for Neurochemistry.