Journal
JOURNAL OF NEUROCHEMISTRY
Volume 132, Issue 6, Pages 713-723Publisher
WILEY
DOI: 10.1111/jnc.13021
Keywords
hypoxia; microglial activation; miR-181c; neuroinflammation; TLR4
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Funding
- National Science Foundation of China [81100795, 81471103, 81371220]
- Shanghai Key Program for Basic Research, Shanghai, China [10JC1404700]
- Health Bureau of Shanghai Municipality, Shanghai, China [2009Y018]
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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.
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