School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Shatin, China.
Institute of Translational and Precision Medicine, Nantong University, Nantong, 226001, China.
Mol Neurobiol. 2024 Apr;61(4):2006-2020. doi: 10.1007/s12035-023-03668-2. Epub 2023 Oct 14.
Both neuroinflammation and iron accumulation play roles in the pathogenesis of Parkinson's disease (PD). However, whether inflammation induces iron dyshomeostasis in dopaminergic neurons at an early stage of PD, at which no quantifiable dopaminergic neuron loss can be observed, is still unknown. As for the inflammation mediators, although several cytokines have been reported to increase in PD, the functions of these cytokines in the SN are double-edged and controversial. In this study, whether inflammation could induce iron dyshomeostasis in dopaminergic neurons through high mobility group protein B1 (HMGB1) in the early stage of PD is explored. Lipopolysaccharide (LPS), a toxin that primarily activates glia cells, and 6-hydroxydopamine (6-OHDA), the neurotoxin that firstly impacts dopaminergic neurons, were utilized to mimic PD in rats. We found a common and exceedingly early over-production of HMGB1, followed by an increase of divalent metal transporter 1 with iron responsive element (DMT1+) in the dopaminergic neurons before quantifiable neuronal loss. HMGB1 neutralizing antibody suppressed inflammation in the SN, DMT1+ elevation in dopaminergic neurons, and dopaminergic neuronal loss in both LPS and 6-OHDA administration- induced PD models. On the contrary, interleukin-1β inhibitor diacerein failed to suppress these outcomes induced by 6-OHDA. Our findings not only demonstrate that inflammation could be one of the causes of DMT1+ increase in dopaminergic neurons, but also highlight HMGB1 as a pivotal early mediator of inflammation-induced iron increase and subsequent neurodegeneration, thereby HMGB1 could serve as a potential target for early-stage PD treatment.
神经炎症和铁积累都在帕金森病（PD）的发病机制中起作用。然而，在 PD 的早期阶段，即尚未观察到可量化的多巴胺神经元损失时，炎症是否会导致多巴胺神经元中铁的动态平衡紊乱仍不清楚。至于炎症介质，尽管已经报道了几种细胞因子在 PD 中增加，但这些细胞因子在 SN 中的作用是双刃剑，存在争议。在这项研究中，探讨了炎症是否可以通过 PD 早期的高迁移率族蛋白 B1（HMGB1）诱导多巴胺神经元中铁的动态平衡紊乱。脂多糖（LPS），一种主要激活神经胶质细胞的毒素，和 6-羟多巴胺（6-OHDA），首先影响多巴胺神经元的神经毒素，被用来模拟大鼠的 PD。我们发现 HMGB1 的过度产生是共同的，并且在可量化的神经元损失之前，多巴胺神经元中就已经出现了二价金属转运蛋白 1 和铁反应元件（DMT1+）的增加。HMGB1 中和抗体抑制了 SN 中的炎症、多巴胺神经元中 DMT1+的升高以及 LPS 和 6-OHDA 给药诱导的 PD 模型中的多巴胺神经元丢失。相反，白细胞介素-1β抑制剂二乙酰水杨酸未能抑制 6-OHDA 引起的这些结果。我们的发现不仅表明炎症可能是多巴胺神经元中 DMT1+增加的原因之一，而且还强调了 HMGB1 作为炎症诱导的铁增加和随后的神经退行性变的关键早期介质，从而 HMGB1 可以作为早期 PD 治疗的潜在靶点。
