荔枝核多酚通过 LRP1/AMPK 介导的自噬诱导抑制 Aβ诱导的 NLRP3 炎性体激活。
Lychee seed polyphenol inhibits Aβ-induced activation of NLRP3 inflammasome via the LRP1/AMPK mediated autophagy induction.
机构信息
Sichuan Key Medical Laboratory of New Drug Discovery and Druggability Evaluation, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, Southwest Medical University, Luzhou, 646000, China.
Sichuan Key Medical Laboratory of New Drug Discovery and Druggability Evaluation, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, Southwest Medical University, Luzhou, 646000, China; Department of Human Anatomy, School of Preclinical Medicine, Southwest Medical University, Luzhou, Sichuan, China.
出版信息
Biomed Pharmacother. 2020 Oct;130:110575. doi: 10.1016/j.biopha.2020.110575. Epub 2020 Aug 5.
Emerging evidence indicates that the enhancement of microglial autophagy inhibits the NLRP3 inflammasome mediated neuroinflammation in Alzheimer's disease (AD). Meanwhile, low density lipoprotein receptor-related protein 1 (LRP1) highly expressed in microglia is able to negatively regulate neuroinflammation and positively regulate autophagy. In addition, we have previously reported that an active lychee seed fraction enriching polyphenol (LSP) exhibits anti-neuroinflammation in Aβ-induced BV-2 cells. However, its molecular mechanism of action is still unclear. In this study, we aim to investigate whether LSP inhibits the NLRP3 inflammasome mediated neuroinflammation and clarify its molecular mechanism in Aβ-induced BV-2 cells and APP/PS1 mice. The results showed that LSP dose- and time-dependently activated autophagy by increasing the expression of Beclin 1 and LC3II in BV-2 cells, which was regulated by the upregulation of LRP1 and its mediated AMPK signaling pathway. In addition, both the Western blotting and fluorescence microscopic results demonstrated that LSP could significantly suppress the activation of NLRP3 inflammasome by inhibiting the expression of NLRP3, ASC, the cleavage of caspase-1, and the release of IL-1β in Aβ(1-42)-induced BV-2 cells. In addition, the siRNA LRP1 successfully abolished the effect of LSP on the activation of AMPK and its mediated autophagy, as well as the inhibition of NLRP3 inflammasome. Furthermore, LSP rescued PC-12 cells which were induced by the conditioned medium from Aβ(1-42)-treated BV-2 cells. Moreover, LSP improved the cognitive function and inhibited the NLRP3 inflammasome in APP/PS1 mice. Taken together, LSP inhibited the NLRP3 inflammasome-mediated neuroinflammation in the in vitro and in vivo models of AD, which was closely associated with the LRP1/AMPK-mediated autophagy. Thus, the findings from this study further provide evidences for LSP serving as a potential drug for the treatment of AD in the future.
新的证据表明，增强小胶质细胞自噬可以抑制阿尔茨海默病（AD）中 NLRP3 炎性体介导的神经炎症。同时，小胶质细胞中高表达的低密度脂蛋白受体相关蛋白 1（LRP1）能够负向调节神经炎症，正向调节自噬。此外，我们之前曾报道过，一种富含多酚的荔枝种子活性部位（LSP）在 Aβ 诱导的 BV-2 细胞中具有抗神经炎症作用。然而，其作用机制尚不清楚。在这项研究中，我们旨在探讨 LSP 是否可以抑制 NLRP3 炎性体介导的神经炎症，并阐明其在 Aβ 诱导的 BV-2 细胞和 APP/PS1 小鼠中的分子机制。结果表明，LSP 通过增加 BV-2 细胞中 Beclin 1 和 LC3II 的表达，剂量和时间依赖性地激活自噬，这是由 LRP1 的上调及其介导的 AMPK 信号通路调节的。此外，Western blot 和荧光显微镜结果均表明，LSP 可通过抑制 NLRP3、ASC、caspase-1 的切割和 IL-1β 的释放，显著抑制 Aβ（1-42）诱导的 BV-2 细胞中 NLRP3 炎性体的激活。此外，LRP1 的 siRNA 成功消除了 LSP 对 AMPK 激活及其介导的自噬和 NLRP3 炎性体抑制的作用。此外，LSP 挽救了由 Aβ（1-42）处理的 BV-2 细胞条件培养基诱导的 PC-12 细胞。此外，LSP 改善了 APP/PS1 小鼠的认知功能并抑制了 NLRP3 炎性体。综上所述，LSP 抑制了 AD 的体外和体内模型中 NLRP3 炎性体介导的神经炎症，这与 LRP1/AMPK 介导的自噬密切相关。因此，本研究的结果进一步为 LSP 作为未来治疗 AD 的潜在药物提供了依据。
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