The Neuroimmune Hypothesis of Paraquat: Connecting the Periphery and Brain

帕金森病（PD）是第二大流行的神经退行性疾病， 一种运动障碍，其特征为脑实质中多巴胺能（DA）神经元的进行性丧失 黑鬼大约90-95%的PD病例是散发性的，农药与散发性PD有关 病因学百草枯（Paraquat，PQ）是一种广泛使用的除草剂，许多流行病学研究都与PQ有关 PD风险增加。关于PQ的DA神经毒性存在机制争议，因为 PQ影响大脑的机制和由此产生的神经病理学仍然是一个争论点。 重要的是，PD与外周和脑免疫扰动有关。小胶质细胞，固有免疫细胞 脑细胞在帕金森病中被长期激活。作为神经毒性细胞因子和活性氧的来源 物种，慢性小胶质细胞活化和神经炎症已涉及在启动和 增强体内和体外PD模型中的选择性DA神经毒性。百草枯神经免疫 假设认为小胶质细胞和神经炎症在PQ DA神经病理学中是有罪的。百草枯 在体内和体外激活小胶质细胞，研究表明， 因素改善PQ DA神经病理学。尽管大脑中的PQ水平较低，但先前的研究表明， 主要集中在PQ与脑实质细胞、神经元和胶质细胞的直接相互作用。 重要的是，PQ在肺、肾和肝中显著蓄积，具有毒性。在此，我们建议， PQ信号通过循环损伤相关分子模式对大脑造成外周损伤 （DAMP）发挥有害的中枢神经系统（CNS）作用。初步数据显示， 循环DAMP HMGB 1在PQ如何影响大脑中的作用。因此，我们假设PQ暴露 引起循环HMGB 1，其引起神经炎症和DA神经病理学。因此，我们的具体 目的是：目的1）评估HMGB 1在PQ诱导的神经炎症和神经病理学中的作用;目的2） 表征血管内皮细胞和脑毛细血管在PQ诱导的HMGB 1中的作用， 神经炎症; AIM 3）确定骨髓细胞在PQ诱导的神经炎症中的作用， 神经病理学如果成功，这些发现将揭示农药（PQ）的一种新的外周机制- 诱导的CNS效应，暗示HMGB 1作为慢性CNS效应的潜在治疗靶点， PQ/农药暴露，并提供关键的洞察PD中的周边的作用。

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease and a devastating movement disorder characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra. Approximately 90-95% of PD cases are sporadic and pesticides have been implicated in sporadic PD etiology. Paraquat (PQ) is a widely used herbicide and many epidemiology studies have associated PQ exposure with increased PD risk. Mechanistic controversy exists regarding the DA neurotoxicity of PQ, as the mechanisms through which PQ impacts the brain and the resulting neuropathology remains a point of debate. Importantly, PD is linked to peripheral and brain immune perturbation. Microglia, the resident innate immune cells in the brain, are chronically activated in PD. As a source of neurotoxic cytokines and reactive oxygen species, chronic microglial activation and neuroinflammation have been implicated in the initiation and augmentation of selective DA neurotoxicity in PD models in vivo and in vitro. The paraquat neuroimmune hypothesis holds that microglia and neuroinflammation are culpable in PQ DA neuropathology. Paraquat activates microglia both in vivo and in vitro, where research has shown that the reduction of pro-inflammatory factors ameliorates PQ DA neuropathology. Despite low levels of PQ localized in the brain, previous research has predominantly focused on the direct interaction of PQ with brain parenchymal cells, the neurons and glia. Importantly, PQ accumulates prominently in the lung, kidney, and liver with toxicity. Here, we propose that peripheral damage from PQ signals to the brain through circulating damage associated molecular patterns (DAMPs) to exert deleterious central nervous system (CNS) effects. Preliminary data implicate an important role for the circulating DAMP HMGB1 in how PQ impacts the brain. Thus, we hypothesize that PQ exposure causes circulating HMGB1, which causes neuroinflammation and DA neuropathology. As such, our specific AIMS are to: AIM1) Assess the role of HMGB1 in PQ–induced neuroinflammation & neuropathology; AIM2) characterize the role of vascular endothelial cells and brain capillaries in PQ-induced HMGB1 and neuroinflammation; AIM3) Define the role of myeloid cells in PQ-induced neuroinflammation and neuropathology. If successful, these findings will reveal a novel peripheral mechanism of pesticide (PQ)- induced CNS effects, implicate HMGB1 as a potential therapeutic target for chronic CNS effects after PQ/pesticide exposure, and provide key insight into the role of the periphery in PD.