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SIRT2 Plays Significant Roles in Lipopolysaccharides-Induced Neuroinflammation and Brain Injury in Mice

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Abstract

Several recent studies have suggested seemingly contrasting roles of SIRT2 in inflammation: Our previous cell culture study has indicated that SIRT2 siRNA-produced decrease in SIRT2 levels can lead to significant inhibition of lipopolysaccharides (LPS)-induced activation of BV2 microglia, suggesting that SIRT2 is required for LPS-induced microglial activation. In contrast, some studies have suggested that SIRT2 deficiency can lead to increased inflammation. In our current study, we used a mouse model of neuroinflammation to determine the roles of SIRT2 in LPS-induced inflammation. We found that administration of SIRT2 inhibitor AGK2 can significantly decrease LPS-induced increases in CD11b signals and the mRNA of TNF-α and IL-6. We further found that AGK2 can block LPS-induced nuclear translocation of NFκB. In addition, our study has shown that AGK2 can decrease not only LPS-induced increase in TUNEL signals—a marker of apoptosis-like damage, but also LPS-induced increases in the levels of active Caspase-3 and Bax. Collectively, our current in vivo study, together with our previous cell culture study, has suggested that SIRT2 is required for LPS-induced neuroinflammation and brain injury.

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Acknowledgments

This study was supported by Chinese National Natural Science Foundation Grants #81171098 and #81271305 (to W. Y.), and Chinese National Natural Science Foundation Grants #61227071 (to X. W.).

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Authors and Affiliations

  1. Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, 1954 Huashan Road, Shanghai, 200030, People’s Republic of China

    Ban Wang, Wei Cao, Xunbing Wei & Weihai Ying

  2. Department of Neurology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201999, People’s Republic of China

    Weihai Ying

  3. Cardiology Department, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, People’s Republic of China

    Youjun Zhang

  4. Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA

    James Chen

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  1. Ban Wang
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  2. Youjun Zhang
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  3. Wei Cao
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  4. Xunbing Wei
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Correspondence to Weihai Ying.

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Supplemental Fig. 1

SIRT2 inhibitor AGK2 suppressed LPS-induced microglial activation in mouse brain five days after the dug treatment. (A) Representative immunofluorescence staining for CD11b (green) in the brains five days after the drug administration. Intraventricularly injected LPS (4 μg per mouse) induced a marked increase in the CD11b signals in the brains, which was prevented by simultaneous administration with AGK2 (0.5 μmol or 1 μmol per mouse), assessed at 5 days after the drug administration. (B) Quantifications of the intensity of the CD11b immunofluorescence in the brains. Eight mice in each group. Error bars indicate the standard error of the mean (SEM), ***, p < 0.001. (TIFF 1496 kb)

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Wang, B., Zhang, Y., Cao, W. et al. SIRT2 Plays Significant Roles in Lipopolysaccharides-Induced Neuroinflammation and Brain Injury in Mice. Neurochem Res 41, 2490–2500 (2016). https://doi.org/10.1007/s11064-016-1981-2

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