Inhibition of the hepatic Nlrp3 protects dopaminergic neurons via attenuating systemic inflammation in a MPTP/p mouse model of Parkinson's disease.
Inhibition of the hepatic Nlrp3 protects dopaminergic neurons via attenuating systemic inflammation in a MPTP/p mouse model of Parkinson's disease.
复制标题
抑制肝脏 Nlrp3 通过减轻帕金森病 MPTP/p 小鼠模型的全身炎症来保护多巴胺能神经元
DOI：
10.1186/s12974-018-1236-z
复制
发表时间：
2018-07-02
影响因子：
9.3
通讯作者：
Hu G
中科院分区：
文献类型：
--
作者：
Qiao C;Zhang Q;Jiang Q;Zhang T;Chen M;Fan Y;Ding J;Lu M;Hu G
帕金森病 (PD) 是一种神经退行性疾病，伴有多巴胺能 (DA) 神经元进行性丧失。全身炎症会引发并加剧黑质中的 DA 神经元变性。在帕金森病患者受影响的大脑区域内和周围检测到来自周围组织的免疫细胞的浸润和转化。我们前期的研究表明，小胶质细胞Nod样受体蛋白（NLRP）3炎症小体在PD发病机制中发挥着至关重要的作用。然而，外周炎症与 DA 神经元死亡之间的直接联系仍然不清楚。在本研究中，我们检测了中脑、肝脏和骨髓来源的巨噬细胞响应 1-甲基-4-苯基-1,2,3,6-四氢吡啶 (MPTP) 急性和慢性攻击的 NLRP3 表达。然后，我们通过尾静脉注射慢病毒包裹的 Nlrp3-siRNA，通过免疫组化、ELISA 和 Western blotting 分析，探讨肝脏 NLRP3 炎症小体介导的炎症对 PD 小鼠模型神经元损伤的潜在影响。我们发现 siNlrp3 下调了小鼠肝脏中 NLRP3 蛋白的表达并抑制了 NLRP3 炎症小体的激活。尾静脉注射 LV3-siNlrp3 减少了肝脏促炎细胞因子的产生，从而减轻了 MPTP 触发的小胶质细胞激活和中脑 DA 神经元损失。这些发现表明，抑制肝脏 NLRP3 炎症小体会削弱炎症细胞因子扩散到大脑中，并延缓神经炎症和 DA 神经元变性的进展。这项研究让我们深入了解了PD发病机制中肝脏炎症和DA神经元损伤之间的直接联系，并为开发PD治疗新药物提供了NLRP3的潜在靶点。本文的在线版本 (10.1186/s12974-018-1236-z) 包含补充材料，可供授权用户使用。
Parkinson’s disease (PD) is a neurodegenerative disorder with progressive loss of dopaminergic (DA) neurons. Systemic inflammation is shown to initiate and exacerbate DA neuronal degeneration in the substantia nigra. The infiltration and transformation of immune cells from the peripheral tissues are detected in and around the affected brain regions of PD patients. Our previous studies demonstrated the crucial role that microglial Nod-like receptor protein (NLRP) 3 inflammasome plays in the pathogenesis of PD. Nevertheless, the direct linkage between peripheral inflammation and DA neuron death remains obscure. In the present study, we detected the NLRP3 expressions in the midbrain, liver, and bone marrow-derived macrophages in response to 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) acute and chronic challenge. We then used a tail vein injection of Nlrp3-siRNA wrapped with lentivirus to explore the potential influence of hepatic NLRP3 inflammasome-mediated inflammation on neuronal injury in a mouse model of PD via immunohistochemistry, ELISA, and Western blotting analysis. We showed that siNlrp3 downregulated the NLRP3 protein expression and inhibited the activation of NLRP3 inflammasomes in mice livers. The tail vein injection of LV3-siNlrp3 reduced the liver pro-inflammatory cytokine production, which subsequently alleviated MPTP-triggered microglial activation and DA neuron loss in the midbrain. These findings indicated that inhibition of hepatic NLRP3 inflammasome weakens inflammatory cytokines spreading into the brain and delays the progress of neuroinflammation and DA neuronal degeneration. This study gives us an insight into the direct linkage between liver inflammation and DA neuron damage in the pathogenesis of PD and provides the potential target of NLRP3 for developing novel drugs for PD therapy. The online version of this article (10.1186/s12974-018-1236-z) contains supplementary material, which is available to authorized users.
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影响因子：
3.9
作者：
EKSTROM, G;DIMONTE, D;SMITH, MT
通讯作者：
SMITH, MT
周围神经病与帕金森氏病更频繁的跌倒有关。
影响因子：
4.1
作者：
Beaulieu ML;Müller MLTM;Bohnen NI
通讯作者：
Bohnen NI
影响因子：
8.7
作者：
Elliott EI;Sutterwala FS
通讯作者：
Sutterwala FS
DOI：
10.1073/pnas.1714948115
发表时间：
2018-02-06
影响因子：
11.1
作者：
Pare, Alexandre;Mailhot, Benoit;Lacroix, Steve
通讯作者：
Lacroix, Steve
影响因子：
5
作者：
Seo, Min-Jong;Hong, Jeong-Min;Lee, Sun-Mee
通讯作者：
Lee, Sun-Mee