Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran.
Research Center for Immunodeficiencies, Children's Medical Center Hospital, Tehran University of Medical Sciences, Dr. Qarib St, Keshavarz Blvd, Tehran, 14194, Iran.
J Neuroinflammation. 2022 Jun 6;19(1):135. doi: 10.1186/s12974-022-02496-w.
Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder, characterized by motor and non-motor symptoms, significantly affecting patients' life. Pathologically, PD is associated with the extensive degeneration of dopaminergic neurons in various regions of the central nervous system (CNS), specifically the substantia nigra. This neuronal loss is accompanied by the aggregation of misfolded protein, named α-synuclein.
Recent studies detected several clues of neuroinflammation in PD samples using postmortem human PD brains and various PD animal models. Some evidence of neuroinflammation in PD patients included higher levels of proinflammatory cytokines in serum and cerebrospinal fluid (CSF), presence of activated microglia in various brain regions such as substantia nigra, infiltration of peripheral inflammatory cells in affected brain regions, and altered function of cellular immunity like monocytes phagocytosis defects. On the other side, Toll-like receptors (TLRs) are innate immune receptors primarily located on microglia, as well as other immune and non-immune cells, expressing pivotal roles in recognizing exogenous and endogenous stimuli and triggering inflammatory responses. Most studies indicated an increased expression of TLRs in the brain and peripheral blood cells of PD samples. Besides, this upregulation was associated with excessive neuroinflammation followed by neurodegeneration in affected regions. Therefore, evidence proposed that TLR-mediated neuroinflammation might lead to a dopaminergic neural loss in PD patients. In this regard, TLR2, TLR4, and TLR9 have the most prominent roles.
Although the presence of inflammation in acute phases of PD might have protective effects concerning the clearance of α-synuclein and delaying the disease advancement, the chronic activation of TLRs and neuroinflammation might lead to neurodegeneration, resulting in the disease progression. Therefore, this study aimed to review additional evidence of the contribution of TLRs and neuroinflammation to PD pathogenesis, with the hope that TLRs could serve as novel disease-modifying therapeutic targets in PD patients in the future.
帕金森病（PD）是第二大常见的神经退行性疾病，其特征为运动和非运动症状，严重影响患者的生活。从病理学角度来看，PD 与中枢神经系统（CNS）各个区域多巴胺能神经元的广泛退化有关，特别是黑质。这种神经元丢失伴随着错误折叠蛋白的聚集，这种蛋白被命名为α-突触核蛋白。
最近的研究使用死后 PD 人脑和各种 PD 动物模型在 PD 样本中检测到了一些神经炎症的线索。PD 患者神经炎症的一些证据包括血清和脑脊液（CSF）中促炎细胞因子水平升高、黑质等各种脑区的活化小胶质细胞存在、受影响脑区外周炎性细胞浸润以及细胞免疫功能改变，如单核细胞吞噬作用缺陷。另一方面，Toll 样受体（TLR）是先天免疫受体，主要位于小胶质细胞以及其他免疫和非免疫细胞上，在识别外源性和内源性刺激物并引发炎症反应方面发挥着关键作用。大多数研究表明，PD 样本的大脑和外周血细胞中 TLR 的表达增加。此外，这种上调与受影响区域过度的神经炎症和随后的神经退行性变有关。因此，有证据表明 TLR 介导的神经炎症可能导致 PD 患者多巴胺能神经元丢失。在这方面，TLR2、TLR4 和 TLR9 具有最突出的作用。
虽然 PD 急性阶段的炎症可能对清除α-突触核蛋白和延缓疾病进展有保护作用，但 TLR 的慢性激活和神经炎症可能导致神经退行性变，从而导致疾病进展。因此，本研究旨在综述 TLR 和神经炎症对 PD 发病机制的额外证据，希望 TLR 能够成为未来 PD 患者新型疾病修饰治疗靶点。
