Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, China.
Department of Clinical Pharmacy, Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, 212001, Jiangsu, China.
J Neuroinflammation. 2018 Jul 2;15(1):193. doi: 10.1186/s12974-018-1236-z.
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.
帕金森病（PD）是一种神经退行性疾病，其特征是多巴胺能（DA）神经元进行性丧失。全身炎症被证明会引发并加剧黑质中 DA 神经元的退行性变。在 PD 患者受影响的大脑区域及其周围，检测到免疫细胞从外周组织的浸润和转化。我们之前的研究表明，小胶质细胞 Nod 样受体蛋白（NLRP）3 炎性体在 PD 发病机制中的关键作用。然而，外周炎症与 DA 神经元死亡之间的直接联系仍不清楚。
在本研究中，我们检测了对 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）急性和慢性挑战后，中脑、肝脏和骨髓来源的巨噬细胞中 NLRP3 的表达。然后，我们使用包裹在慢病毒中的 Nlrp3-siRNA 进行尾静脉注射，通过免疫组织化学、ELISA 和 Western blot 分析，探讨肝 NLRP3 炎性体介导的炎症对 PD 小鼠模型中神经元损伤的潜在影响。
我们表明，siNlrp3 下调了 NLRP3 蛋白表达并抑制了小鼠肝脏中 NLRP3 炎性体的激活。LV3-siNlrp3 的尾静脉注射减少了肝脏前炎症细胞因子的产生，从而减轻了 MPTP 引发的中脑小胶质细胞激活和 DA 神经元丢失。这些发现表明，抑制肝 NLRP3 炎性体可减弱炎症细胞因子向大脑扩散，并延缓神经炎症和 DA 神经元退行性变的进展。
本研究深入了解了 PD 发病机制中肝脏炎症与 DA 神经元损伤之间的直接联系，并为开发治疗 PD 的新型 NLRP3 药物提供了潜在靶点。
