Department of Pharmacology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
Department of Anesthesiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, 250021, China.
Brain Behav Immun. 2021 Jan;91:324-338. doi: 10.1016/j.bbi.2020.10.010. Epub 2020 Oct 8.
Microglia-mediated inflammation plays an important role in the pathogenesis of several neurodegenerative diseases including Parkinson's disease (PD). Recently, autophagy has been linked to the regulation of the inflammatory response. However, the potential role of microglial autophagy in the context of PD pathology has not been characterized. In the present study, we investigated whether impaired microglial autophagy would affect dopaminergic neurodegeneration and neuroinflammation both in vivo and in vitro. In vitro, BV2 microglial cells were exposed to LPS in the presence or absence of autophagy-related gene 5 (Atg5) small interference RNA (Atg5-siRNA). For in vivo study, microglial Atg5 conditional knockout (Atg5; CX3CR1-Cre) mice and their wild-type littermates (Atg5) were intraperitoneally injected with MPTP to induce experimental PD model. Our results revealed that disruption of autophagy by Atg5-siRNA aggravated LPS-induced inflammatory responses in BV2 cells and caused greater apoptosis in SH-SY5Y cells treated with BV2 conditioned medium. In mice, impaired autophagy in microglia exacerbated dopaminergic neuron loss in response to MPTP. The mechanism by which the deficiency of microglial autophagy promoted neuroinflammation and dopaminergic neurodegeneration was related to the regulation of NLRP3 inflammasome activation. These findings demonstrate that impairing microglial autophagy aggravates pro-inflammatory responses to LPS and exacerbates MPTP-induced neurodegeneration by modulating NLRP3 inflammasome responses. We anticipate that enhancing microglial autophagy may be a promising new therapeutic strategy for PD.
小胶质细胞介导的炎症在包括帕金森病（PD）在内的几种神经退行性疾病的发病机制中起着重要作用。最近，自噬已与炎症反应的调节有关。然而，小胶质细胞自噬在 PD 病理中的潜在作用尚未得到表征。在本研究中，我们研究了小胶质细胞自噬受损是否会影响体内和体外多巴胺能神经退行性变和神经炎症。在体外，将 LPS 暴露于 BV2 小胶质细胞中，同时存在或不存在自噬相关基因 5（Atg5）小干扰 RNA（Atg5-siRNA）。对于体内研究，使用微胶质细胞 Atg5 条件性敲除（Atg5; CX3CR1-Cre）小鼠及其野生型同窝仔（Atg5）经腹腔注射 MPTP 诱导实验性 PD 模型。我们的结果表明，Atg5-siRNA 破坏自噬会加重 LPS 诱导的 BV2 细胞炎症反应，并导致用 BV2 条件培养基处理的 SH-SY5Y 细胞凋亡增加。在小鼠中，小胶质细胞自噬受损加剧了对 MPTP 的多巴胺能神经元丢失的反应。小胶质细胞自噬缺乏促进神经炎症和多巴胺能神经退行性变的机制与 NLRP3 炎性体激活的调节有关。这些发现表明，抑制小胶质细胞自噬会加重 LPS 的促炎反应，并通过调节 NLRP3 炎性体反应加剧 MPTP 诱导的神经退行性变。我们预计增强小胶质细胞自噬可能是 PD 的一种有前途的新治疗策略。
