Micro<scp>RNA</scp>‐181c negatively regulates the inflammatory response in oxygen‐glucose‐deprived microglia by targeting Toll‐like receptor 4

Abstract

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 TLR 4 expression but down‐regulated miR‐181c expression in primary microglia. We also demonstrated that miR‐181c suppresses TLR 4 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 TLR 4 in microglia significantly decreased TLR 4 expression and inhibited NF ‐κB activation and the downstream production of proinflammatory mediators, whereas ectopic TLR 4 expression significantly abrogated the suppressed inflammatory response induced by miR‐181c. Therefore, our study identified an important role for the miR‐181c‐ TLR 4 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. image 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.