Abstract
The activation of microglia is an important cause of central nervous system (CNS) inflammatory cell infiltration and inflammatory demyelination in experimental autoimmune encephalomyelitis (EAE). Furthermore, the proinflammatory response induced by the NLR family pyrin domain containing 3 (NLRP3) inflammasome can be amplified in microglia after NLRP3 inflammasome activation. Autophagy is closely related to the inflammatory response. Caffeine exerts anti-inflammatory and autophagy-stimulating effects, but the specific mechanism remains unclear. This study examined the mechanism underlying the anti-inflammatory effect of caffeine on EAE. In this study, C57BL/6 mice were immunized to induce EAE and treated with caffeine to observe its effect on prognosis. The effects of caffeine on autophagy and inflammation were also analysed in mouse primary microglia (PM) and the BV2 cell line. The data demonstrated that caffeine reduced the clinical score, the infiltration of inflammatory cells, the demyelination level, and the activation of microglia in EAE mice. Furthermore, caffeine increased the LC3-II/LC3-I levels and decreased the NLRP3 and P62 levels in EAE mice, whereas the autophagy inhibitor 3-methylamine (3-MA) blocked these effects. In vitro, caffeine promoted autophagy by suppressing the mechanistic target of rapamycin (mTOR) pathway and inhibited activation of the NLRP3 inflammasome. However, autophagy-related gene 5 (ATG5)-specific siRNA abolished the anti-inflammatory effect of caffeine treatment in PM and BV2 cells. Taken together, these data suggest that caffeine exerts a newly discovered effect on EAE by reducing NLRP3 inflammasome activation via the induction of autophagy in microglia.
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We thank the Laboratory of Pharmacology, Chongqing Medical University for sharing the cell lines in this study.
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This study was supported by the National Natural Science Foundation of China (Grant No. 81771275), the National Natural Science Foundation of China Youth Fund Project (Grant No. 81701191).
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Hui-Qi Wang and Kai-Yi Song: study design, experimental operations, data sorting, statistical analysis, and manuscript preparation; Jin-Zhou Feng and Si-Yuan Huang: study design and experimental operations; Xiu-Ming Guo, Lei Zhang, and Gang Zhang: data sorting and experimental operations; Ying-Chao Huo, Rong-Rong Zhang, Yue Ma, and Qing-Zhe Hu: data sorting, statistical analysis, and experimental operations; Xin-Yue Qin: study design, data analysis, and final manuscript preparation and revision. All authors read and approved the final manuscript.
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Wang, HQ., Song, KY., Feng, JZ. et al. Caffeine Inhibits Activation of the NLRP3 Inflammasome via Autophagy to Attenuate Microglia-Mediated Neuroinflammation in Experimental Autoimmune Encephalomyelitis. J Mol Neurosci 72, 97–112 (2022). https://doi.org/10.1007/s12031-021-01894-8
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DOI: https://doi.org/10.1007/s12031-021-01894-8