Caffeine Inhibits Activation of the NLRP3 Inflammasome via Autophagy to Attenuate Microglia-Mediated Neuroinflammation in Experimental Autoimmune Encephalomyelitis.
Caffeine Inhibits Activation of the NLRP3 Inflammasome via Autophagy to Attenuate Microglia-Mediated Neuroinflammation in Experimental Autoimmune Encephalomyelitis.
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咖啡因通过自噬抑制 NLRP3 炎症小体的激活，以减轻实验性自身免疫性脑脊髓炎中小胶质细胞介导的神经炎症。
DOI：
10.1007/s12031-021-01894-8
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
秦新月
中科院分区：
文献类型：
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作者：
王慧琪;秦新月
实验性自身免疫性脑脊髓炎（EAE）时，小胶质细胞的活化是导致中枢神经系统（CNS）炎性细胞浸润和炎性脱髓鞘的重要原因。此外，由NLR家族pyrin domain containing 3（NLRP 3）炎性体诱导的促炎反应可以在NLRP 3炎性体活化后在小胶质细胞中放大。自噬与炎症反应密切相关。咖啡因具有抗炎和刺激自噬的作用，但具体机制尚不清楚。本研究探讨了咖啡因对EAE的抗炎作用机制。本研究通过免疫C57 BL/6小鼠诱发EAE，并给予咖啡因治疗，观察其对预后的影响。还在小鼠原代小胶质细胞（PM）和BV 2细胞系中分析了咖啡因对自噬和炎症的影响。实验结果表明，咖啡因可降低EAE小鼠的临床评分、炎性细胞浸润、脱髓鞘水平和小胶质细胞的活化。此外，咖啡因增加了EAE小鼠的LC 3-II/LC 3-I水平，降低了NLRP 3和P62水平，而自噬抑制剂3-甲胺（3-MA）阻断了这些作用。在体外，咖啡因通过抑制雷帕霉素（mTOR）通路的机制靶点来促进自噬，并抑制NLRP 3炎性体的活化。然而，自噬相关基因5（ATG 5）特异性siRNA消除了PM和BV 2细胞中咖啡因治疗的抗炎作用。总之，这些数据表明，咖啡因通过诱导小胶质细胞中的自噬来减少NLRP 3炎性小体激活，从而对EAE产生新发现的作用。
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.