Pramipexole inhibits astrocytic NLRP3 inflammasome activation via Drd3-dependent autophagy in a mouse model of Parkinson's disease.
Pramipexole inhibits astrocytic NLRP3 inflammasome activation via Drd3-dependent autophagy in a mouse model of Parkinson's disease.
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普拉克索通过 Drd3 依赖性自噬抑制帕金森病小鼠模型中星形胶质细胞 NLRP3 炎症小体的激活
DOI：
10.1038/s41401-022-00951-1
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发表时间：
2023-01
影响因子：
8.2
通讯作者：
Liu, Chun-Feng
中科院分区：
文献类型：
--
作者：
Dong, An-Qi;Yang, Ya-Ping;Jiang, Shu-Min;Yao, Xiao-Yu;Qi, Di;Mao, Cheng-Jie;Cheng, Xiao-Yu;Wang, Fen;Hu, Li-Fang;Liu, Chun-Feng
炎症是帕金森病（PD）的致病过程之一。多巴胺受体激动剂普拉克索（PPX）是临床上广泛应用于PD治疗的药物。大量研究表明PPX对多巴胺能神经元具有保护作用，但PPX保护DA神经元的分子机制尚未完全阐明。在本研究中，我们研究了PPX是否调制PD相关的神经炎症和潜在的机制。采用双侧纹状体内注射脂多糖（LPS）建立小鼠PD模型。小鼠腹腔注射PPX（0.5mg·kg-1·d-1）。分别在LPS注射前3天和手术后3天或21天进行生物化学和组织学分析。我们发现，PPX给药显著减轻了DA神经元的丢失，抑制了LPS注射小鼠黑质中星形胶质细胞的活化和促炎细胞因子IL-1β的水平。此外，PPX给药显著降低了NLRP 3炎性小体相关蛋白的表达，即，在纹状体中，半胱天冬酶-1、IL-1β和含有半胱天冬酶募集结构域（ASC）的凋亡相关斑点样蛋白的裂解形式。这些结果在体外LPS+ ATP刺激的原代小鼠星形胶质细胞中得到验证。值得注意的是，我们发现PPX（100-400 μM）剂量依赖性地增强了星形胶质细胞中的自噬活性，这通过LC 3-II和BECN 1蛋白表达的升高以及GFP-LC 3斑点形成的增加来证明。PPX对星形胶质细胞NLRP 3炎性小体和自噬的相反作用通过Drd 3耗尽而消除。此外，我们证明了在体外用自噬抑制剂氯喹（40 μM）预处理星形胶质细胞和在体内星形胶质细胞特异性Atg 5敲低都阻断了PPX引起的对NLRP 3炎性小体的抑制和对DA神经元损伤的保护。总之，这项研究证明了PPX通过Drd 3依赖性增强星形胶质细胞中的自噬活性而具有抗神经炎症活性，并揭示了PPX在PD治疗中的有益作用的新机制。
Inflammation is one of the pathogenic processes in Parkinson’s disease (PD). Dopamine receptor agonist pramipexole (PPX) is extensively used for PD treatment in clinics. A number of studies show that PPX exerts neuroprotection on dopaminergic (DA) neurons, but the molecular mechanisms underlying the protective effects of PPX on DA neurons are not fully elucidated. In the present study, we investigated whether PPX modulated PD-related neuroinflammation and underlying mechanisms. PD model was established in mice by bilateral striatum injection of lipopolyssaccharide (LPS). The mice were administered PPX (0.5 mg·kg−1·d−1, i.p.) 3 days before LPS injection, and for 3 or 21 days after surgery, respectively, for biochemical and histological analyses. We showed that PPX administration significantly alleviated the loss of DA neurons, and suppressed the astrocyte activation and levels of proinflammatory cytokine IL-1β in the substantia nigra of LPS-injected mice. Furthermore, PPX administration significantly decreased the expression of NLRP3 inflammasome-associated proteins, i.e., cleaved forms of caspase-1, IL-1β, and apoptosis-associated speck-like protein containing a caspase recruit domain (ASC) in the striatum. These results were validated in LPS+ATP-stimulated primary mouse astrocytes in vitro. Remarkably, we showed that PPX (100–400 μM) dose-dependently enhanced the autophagy activity in the astrocytes evidenced by the elevations in LC3-II and BECN1 protein expression, as well as the increase of GFP-LC3 puncta formation. The opposite effects of PPX on astrocytic NLRP3 inflammasome and autophagy were eliminated by Drd3 depletion. Moreover, we demonstrated that both pretreatment of astrocytes with autophagy inhibitor chloroquine (40 μM) in vitro and astrocyte-specific Atg5 knockdown in vivo blocked PPX-caused inhibition on NLRP3 inflammasome and protection against DA neuron damage. Altogether, this study demonstrates an anti-neuroinflammatory activity of PPX via a Drd3-dependent enhancement of autophagy activity in astrocytes, and reveals a new mechanism for the beneficial effect of PPX in PD therapy.
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影响因子：
48
作者：
Barone, Paolo;Poewe, Werner;Weintraub, Daniel
通讯作者：
Weintraub, Daniel
影响因子：
9.3
作者：
Fan, Zheng;Pan, Yu-Ting;Wang, Xiao-Min
通讯作者：
Wang, Xiao-Min
影响因子：
9.3
作者：
Montoya, Andro;Elgueta, Daniela;Pacheco, Rodrigo
通讯作者：
Pacheco, Rodrigo
影响因子：
4.2
作者：
Hunter, Randy L.;Cheng, Baohua;Choi, Dong-Young;Liu, Mei;Liu, Shuwei;Cass, Wayne A.;Bing, Guoying
通讯作者：
Bing, Guoying
影响因子：
4.4
作者：
Deng, Chao;Zhu, Jianping;Dai, Li
通讯作者：
Dai, Li