• Yanning Li, Yujie Ma, Lijie Gao, Ting Wang, Yuchen Zhuang, Yuping Zhang, Long Zheng, and Xifu Liu.
• Center for Drug Discovery Innovation, College of Life Science, Hebei Normal University, Shijiazhuang 050024, Hebei, People's Republic of China; Department of Molecular Biology, Hebei Key Lab of Laboratory Animal Science, Hebei Medical University, Shijiazhuang 050017, Hebei, People's Republic of China. Electronic address: liyanning1981@126.com.
• Neuroscience. 2023 Aug 21; 526: 859685-96.

AbstractVitamin D3 may suppress microglial activation and neuroinflammation, which play a central role in the pathophysiology of many neurological disorders. Sirt6 can remove histone 3 lysine 9 acetylation (H3K9ac) to repress expression of pathological genes and produce anti-inflammatory effects. However, whether vitamin D3 upregulates microglial Sirt6 to exert its protective effects against microglial activation and neuroinflammation is unclear. The effects of lower, normal, and higher dosages (1, 10 and 100 μg/kg/day) of vitamin D3 on behavioral and neuromorphological changes, brain inflammatory factors, Sirt6 and H3K9ac levels, and microglial Sirt6 distribution in hippocampus were evaluated in lipopolysaccharide (LPS)-stimulated mice. In addition, the effects of vitamin D3 on inflammatory factors, reactive oxygen species, Sirt6, and H3K9ac were confirmed in LPS-stimulated BV-2 cells. We verified that vitamin D3 ameliorated the impaired sociability of LPS-stimulated mice by three-chamber test. In addition, vitamin D3 upregulated brain Sirt6 generation, reduced H3K9ac levels and inhibited generation of brain inflammatory factors. Moreover, vitamin D3 promoted microglial Sirt6 distribution and attenuated microglia displaying an activated morphology in the hippocampus of LPS-stimulated mice. Similarly, vitamin D3 upregulated Sirt6 generation and intensity, reduced H3K9ac levels, and inhibited the inflammatory activation of LPS-stimulated BV-2 cells. In conclusion, vitamin D3 may upregulate microglial Sirt6 to reduce H3K9ac and inhibit microglial activation, thereby antagonizing neuroinflammation.Copyright © 2023 IBRO. Published by Elsevier Ltd. All rights reserved.

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