MicroRNA-181c negatively regulates the inflammatory response in oxygen-glucose-deprived microglia by targeting Toll-like receptor 4

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)-alpha 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 30-untranslated region. In addition, miR-181c inhibited NF-jB activation and the downstream production of proinflammatory mediators, such as TNF-alpha, IL1b, and iNOS. Knocking down TLR4 in microglia significantly decreased TLR4 expression and inhibited NF-jB 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.