Department of Neurobiology, School of Basic Medical Sciences, Beijing Institute for Brain Disorders and Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, Capital Medical University, Beijing 100069, China.
Burke Medical Research Institute, Weill Cornell Medicine, White Plains, NY, 10605, USA.
Brain Behav Immun. 2018 Jul;71:93-107. doi: 10.1016/j.bbi.2018.04.006. Epub 2018 Apr 9.
Metabotropic glutamate receptor (mGlu) regulates microglia activation, which contributes to inflammation. However, the role of mGlu in neuroinflammation associated with Parkinson's disease (PD) remains unclear. Triptolide (T10) exerts potent immunosuppressive and anti-inflammatory effects and protects neurons by inhibiting microglia activation. In this study, we investigated the role of mGlu in the anti-inflammatory effect of T10 in a lipopolysaccharide (LPS)-induced PD model. In cultured BV2 cells and primary microglia, blocking mGlu activity or knocking down its expression abolished T10-inhibited release of proinflammatory cytokines induced by LPS. Moreover, T10 up-regulated mGlu expression decreased by LPS through enhancing mRNA expression and protein stability. T10 also reversed the reduction in mGlu membrane localization and modulated receptor-mediated mitogen-activated protein kinase activity induced by LPS. Pharmacological inhibition of signaling molecules increased nitric oxide level and inducible nitric oxide synthase (iNOS), tumor necrosis factor-α, and interleukin (IL)-1β and -6 transcript levels that were downregulated by treatment with T10. Consistent with these in vitro findings, blocking mGlu attenuated the anti-inflammatory effects of T10 in an LPS-induced PD model and blocked the decreases in the number and morphology of ionized calcium binding adaptor molecule 1-positive microglia and LPS-induced iNOS protein expression caused by T10 treatment. Besides, mGlu mediated the effect of T10 on microglia-induced astrocyte activation in vitro and in vivo. The findings provide evidence for a novel mechanism by which mGlu regulates T10-inhibited microglia activation via modulating protein expression of the receptor and its intracellular signaling. The study might contribute to the biological effects of Chinese herbs as an approach for protecting against neurotoxicity in PD.
代谢型谷氨酸受体（mGlu）调节小胶质细胞激活，从而导致炎症。然而，mGlu 在与帕金森病（PD）相关的神经炎症中的作用尚不清楚。雷公藤红素（T10）具有强大的免疫抑制和抗炎作用，并通过抑制小胶质细胞激活来保护神经元。在这项研究中，我们研究了 mGlu 在 T10 抑制脂多糖（LPS）诱导的 PD 模型中小胶质细胞激活的抗炎作用中的作用。在培养的 BV2 细胞和原代小胶质细胞中，阻断 mGlu 活性或敲低其表达可消除 T10 抑制 LPS 诱导的促炎细胞因子释放。此外，T10 通过增强 mRNA 表达和蛋白稳定性来上调 LPS 下调的 mGlu 表达。T10 还逆转了 LPS 诱导的 mGlu 膜定位减少和受体介导的丝裂原活化蛋白激酶活性的调节。信号分子的药理学抑制增加了一氧化氮水平和诱导型一氧化氮合酶（iNOS）、肿瘤坏死因子-α 和白细胞介素（IL）-1β 和 -6 的转录水平，这些水平被 T10 处理下调。与这些体外发现一致，阻断 mGlu 减弱了 T10 在 LPS 诱导的 PD 模型中的抗炎作用，并阻止了 LPS 诱导的小胶质细胞激活减少以及 T10 处理引起的离子钙结合接头分子 1 阳性小胶质细胞数量和形态的减少和 iNOS 蛋白表达的减少。此外，mGlu 介导了 T10 对体外和体内小胶质细胞诱导的星形胶质细胞激活的作用。这些发现为 mGlu 通过调节受体及其细胞内信号转导的蛋白表达来调节 T10 抑制小胶质细胞激活的新机制提供了证据。该研究可能为中药作为保护 PD 神经毒性的一种方法提供了生物学依据。
