TLR4/NF-κB通路调控小胶质细胞极化在帕金森病中的作用机制及中西医防治研究进展^*

Mechanistic insights into TLR4/NF-κB -mediated microglial polarization in Parkinson's disease and advances in integrated traditional Chinese and Western medicine-based interventions

摘要

帕金森病(PD)以黑质多巴胺能神经元丢失及α-突触核蛋白(α-syn)异常聚集为核心病理特征,神经炎症是其病程进展的关键驱动因素。Toll样受体4/核因子κB(TLR4/NF-κB)通路作为调控小胶质细胞极化的核心机制,通过介导α-syn清除、肠-脑轴信号传递及NOD样受体家族含pyrin结构域的蛋白3(NLRP3)炎症小体激活参与神经炎症与神经退行样变化。该通路过度激活促使小胶质细胞向促炎M1表型极化,加剧多巴胺能神经元损伤;靶向抑制则可诱导小胶质细胞向抗炎M2表型极化,发挥神经保护作用。目前,靶向该通路的西药、中药单体或复方及针灸等中西医防治策略已获初步验证,但机制仍需深化。本文拟对TLR4/NF-κB通路调控小胶质细胞极化的分子机制及其在PD发病中的多维度作用,以及靶向该通路的中西药及针灸等防治策略作一综述,为PD多维度干预提供理论支撑。

Abstract

Parkinson's disease (PD) is pathologically defined by the degeneration of dopaminergic neurons in the substantia nigra and the aberrant accumulation of α-synuclein (α-syn), with neuroinflammation serving as a principal factor in disease advancement. The TLR4/NF-κB pathway, a fundamental mechanism governing microglial polarization, is involved in neuroinflammation and neurodegeneration through the mediation of α-syn clearance, gut-brain axis signaling, and NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation; its hyperactivation drives microglial polarization towards the pro-inflammatory M1 phenotype, worsening dopaminergic neuronal injury, whereas targeted inhibition encourages polarization towards the anti-inflammatory M2 phenotype, providing neuroprotective benefits. Presently, integrated techniques combining traditional Chinese and Western therapy that target this pathway—such as conventional pharmaceuticals, Chinese herbal monomers/compounds, and acupuncture—have undergone preliminary validation; nonetheless, their processes necessitate more elucidation. This review comprehensively details the molecular mechanisms of TLR4/NF-κB pathway-mediated microglial polarization and its multifaceted roles in PD pathogenesis, while summarizing interventions from both Chinese and Western medicine that target this pathway, thereby offering theoretical support for multidimensional interventions in PD.

关键词

帕金森病 / Toll样受体4/核因子κB / 小胶质细胞 / 神经炎症 / 中西医结合治疗

Key words

Parkinson's disease / Toll-like receptor 4/Nuclear factor κB / Microglia / Neuroinflammation / Integrated traditional Chinese and Western medicine

[1] George S, Brundin P. Immunotherapy in Parkinson's disease: micromanaging alpha-synuclein aggregation[J]. J Parkinsons Dis, 2015, 5(3): 413-424.
[2] Ben-Shlomo Y, Darweesh S, Llibre-Guerra J, et al. The epidemiology of Parkinson's disease[J]. Lancet, 2024, 403(10423): 283-292.
[3] Tansey M G, Wallings R L, Houser M C, et al. Inflammation and immune dysfunction in Parkinson disease[J]. Nat Rev Immunol, 2022, 22(11): 657-673.
[4] Sanjay, Park M, Lee H J. Roles of fatty acids in microglial polarization: evidence from in vitro and in vivo studies on neurodegenerative diseases[J]. Int J Mol Sci, 2022, 23(13): 7300.
[5] Masuda T, Prinz M. Microglia: a unique versatile cell in the central nervous system[J]. ACS Chem Neurosci, 2016, 7(4): 428-434.
[6] Yu H, Chang Q, Sun T, et al. Metabolic reprogramming and polarization of microglia in Parkinson's disease: role of inflammasome and iron[J]. Ageing Res Rev, 2023, 90: 102032.
[7] Choi I, Zhang Y, Seegobin S P, et al. Microglia clear neuron-released α-synuclein via selective autophagy and prevent neurodegeneration[J]. Nat Commun, 2020, 11(1): 1386.
[8] Gao C, Jiang J, Tan Y, et al. Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets[J]. Signal Transduct Target Ther, 2023, 8(1): 359.
[9] Keren-Shaul H, Spinrad A, Weiner A, et al. A unique microglia type associated with restricting development of Alzheimer's disease[J]. Cell, 2017, 169(7): 1276-1290.e17.
[10]Wang M, Pan W, Xu Y, et al. Microglia-mediated neuroinflammation: a potential target for the treatment of cardiovascular diseases[J]. J Inflamm Res, 2022, 15: 3083-3094.
[11]Zhou Y, Song W M, Andhey P S, et al. Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer's disease[J]. Nat Med, 2020, 26(1): 131-142.
[12]Duan T, Du Y, Xing C, et al. Toll-like receptor signaling and its role in cell-mediated immunity[J]. Front Immunol, 2022, 13: 812774.
[13]赵梦洁, 赵琼, 杨翠玲, 等. 加味泻黄散对抽动障碍大鼠小胶质细胞极化及TLR4/MyD88/NF-κB通路的影响[J]. 中国实验方剂学杂志, 2025, 31(4): 10-18.
Zhao M J, Zhao Q, Yang C L, et al. Modified Xiehuangsan regulates microglial polarization and TLR4/MyD88/NF-κB pathway to treat tic disorders in rats[J]. Chin J Exp Tradit Med Formulae, 2025, 31(4): 10-18.
[14]Zhang B, Lian W, Zhao J, et al. DL0410 alleviates memory impairment in D-galactose-induced aging rats by suppressing neuroinflammation via the TLR4/MyD88/NF-κB pathway[J]. Oxid Med Cell Longev, 2021, 2021: 6521146.
[15]Tresse E, Marturia-Navarro J, Sew W Q G, et al. Mitochondrial DNA damage triggers spread of Parkinson's disease-like pathology[J]. Mol Psychiatry, 2023, 28(11): 4902-4914.
[16]Zhang X, Sun D, Zhou X, et al. Proinflammatory S100A9 stimulates TLR4/NF-κB signaling pathways causing enhanced phagocytic capacity of microglial cells[J]. Immunol Lett, 2023, 255: 54-61.
[17]Gan P, Ding L, Hang G, et al. Oxymatrine attenuates dopaminergic neuronal damage and microglia-mediated neuroinflammation through cathepsin D-dependent HMGB1/TLR4/NF-κB pathway in Parkinson's disease[J]. Front Pharmacol, 2020, 11: 776.
[18]Lv H, Tan L, Miao Y, et al. Machine learning identifies lactate metabolism biomarkers and deciphers immune infiltration landscapes in Parkinson's disease[J]. Sci Rep, 2025, 15(1): 37665.
[19]Merlini M, Rafalski V A, Rios Coronado P E, et al. Fibrinogen induces microglia-mediated spine elimination and cognitive impairment in an Alzheimer's disease model[J]. Neuron, 2019, 101(6): 1099-1108.e6.
[20]裴晓雪, 陈珈萱, 宋传锦, 等. 脂质成分与代谢在帕金森病发生中的研究进展[J]. 国际老年医学杂志, 2024, 45(6): 723-728.
Pei X X, Chen J X, Song C J, et al. Insights into lipid metabolism and composition in Parkinson's disease pathogenesis[J]. Int J Geriatr, 2024, 45(6): 723-728.
[21]Stefanova N, Fellner L, Reindl M, et al. Toll-like receptor 4 promotes α-synuclein clearance and survival of nigral dopaminergic neurons[J]. Am J Pathol, 2011, 179(2): 954-963.
[22]Doorn K J, Moors T, Drukarch B, et al. Microglial phenotypes and toll-like receptor 2 in the substantia nigra and hippocampus of incidental Lewy body disease cases and Parkinson's disease patients[J]. Acta Neuropathol Commun, 2014, 2: 90.
[23]Zhang Z, Liu Z, Lv A, et al. How Toll-like receptors influence Parkinson's disease in the microbiome-gut-brain axis[J]. Front Immunol, 2023, 14: 1154626.
[24]Kustrimovic N, Balkhi S, Bilato G, et al. Gut microbiota and immune system dynamics in Parkinson's and Alzheimer's diseases[J]. Int J Mol Sci, 2024, 25(22): 12164.
[25]丁鸿莉, 第五永长, 刘奇, 等. 微生物-肠-脑轴与阿尔茨海默病相关性的研究进展[J]. 国际老年医学杂志, 2023, 44(1): 87-90.
Ding H L, Diwu Y C, Liu Q, et al. Research progress on the correlation between microbiota-gut-brain axis and Alzheimer's disease[J]. Int J Geriatr, 2023, 44(1): 87-90.
[26]Sui Y T, Bullock K M, Erickson M A, et al. Alpha synuclein is transported into and out of the brain by the blood-brain barrier[J]. Peptides, 2014, 62: 197-202.
[27]Perez-Pardo P, Dodiya H B, Engen P A, et al. Role of TLR4 in the gut-brain axis in Parkinson's disease: a translational study from men to mice[J]. Gut, 2019, 68(5): 829-843.
[28]Mu C, Zhou Z, Li J, et al. GDNF signaling modulation by Akkermansia muciniphila ameliorates constipation-depression comorbidity in Parkinson's disease[J]. NPJ Parkinsons Dis, 2025, 11(1): 342.
[29]Erny D, Hrabě de Angelis A L, Jaitin D, et al. Host microbiota constantly control maturation and function of microglia in the CNS[J]. Nat Neurosci, 2015, 18(7): 965-977.
[30]Sampson T R, Debelius J W, Thron T, et al. Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson's disease[J]. Cell, 2016, 167(6): 1469-1480.e12.
[31]Margolis K G, Cryan J F, Mayer E A. The microbiota-gut-brain axis: from motility to mood[J]. Gastroenterology, 2021, 160(5): 1486-1501.
[32]Xu W, Huang Y, Zhou R. NLRP3 inflammasome in neuroinflammation and central nervous system diseases[J]. Cell Mol Immunol, 2025, 22(4): 341-355.
[33]Swanson K V, Deng M, Ting J P. The NLRP3 inflammasome: molecular activation and regulation to therapeutics[J]. Nat Rev Immunol, 2019, 19(8): 477-489.
[34]Yan Y Q, Zheng R, Liu Y, et al. Parkin regulates microglial NLRP3 and represses neurodegeneration in Parkinson's disease[J]. Aging Cell, 2023, 22(6): e13834.
[35]Lee E, Hwang I, Park S, et al. MPTP-driven NLRP3 inflammasome activation in microglia plays a central role in dopaminergic neurodegeneration[J]. Cell Death Differ, 2019, 26(2): 213-228.
[36]Fan Z, Pan Y T, Zhang Z Y, et al. Systemic activation of NLRP3 inflammasome and plasma α-synuclein levels are correlated with motor severity and progression in Parkinson's disease[J]. J Neuroinflammation, 2020, 17(1): 11.
[37]Tian Y, Chen R, Su Z. HMGB1 is a potential and challenging therapeutic target for Parkinson's disease[J]. Cell Mol Neurobiol, 2023, 43(1): 47-58.
[38]Yang H, Wang H, Ju Z, et al. MD-2 is required for disulfide HMGB1-dependent TLR4 signaling[J]. J Exp Med, 2015, 212(1): 5-14.
[39]Liu T, Wang P, Yin H, et al. Rapamycin reverses ferroptosis by increasing autophagy in MPTP/MPP(+)-induced models of Parkinson's disease[J]. Neural Regen Res, 2023, 18(11): 2514-2519.
[40]Shi L, Liu S, Chen J, et al. Microglial polarization pathways and therapeutic drugs targeting activated microglia in traumatic brain injury[J]. Neural Regen Res, 2026, 21(1): 39-56.
[41]Decressac M, Mattsson B, Weikop P, et al. TFEB-mediated autophagy rescues midbrain dopamine neurons from α-synuclein toxicity[J]. Proc Natl Acad Sci USA, 2013, 110(19): E1817-E1826.
[42]Su Q, Ng W L, Goh S Y, et al. Targeting the inflammasome in Parkinson's disease[J]. Front Aging Neurosci, 2022, 14: 957705.
[43]Gordon R, Albornoz E A, Christie D C, et al. Inflammasome inhibition prevents α-synuclein pathology and dopaminergic neurodegeneration in mice[J]. Sci Transl Med, 2018, 10(465): eaah4066.
[44]Yang L, Huang H, Fan Y, et al. Astragaloside IV ameliorates Parkinson's disease by inhibiting TLR4/NF-κB-dependent neuroinflammation[J]. Int Immunopharmacol, 2025, 160: 114972.
[45]Zhang C, Zhou J, Zhuo L, et al. The TLR4/NF-κB/NLRP3 and Nrf2/HO-1 pathways mediate the neuroprotective effects of alkaloids extracted from Uncaria rhynchophylla in Parkinson's disease[J]. J Ethnopharmacol, 2024, 333: 118391.
[46]崔拓拓, 曹俊岭, 欧阳竞锋, 等. 大定风珠对帕金森病模型小鼠脑黑质小胶质细胞活化及TLR4/MyD88/NF-κB信号通路的影响[J]. 中医杂志, 2023, 64(9): 930-938.
Cui T T, Cao J L, Ouyang J F, et al. Effect and Dadingfengzhu pill on the activation of microglial cells in the substantia nigra and TLR4/MyD88/NF-κB signaling pathway in Parkinson's disease model mice[J]. J Tradit Chin Med, 2023, 64(9): 930-938.
[47]谌盈帆, 栾振先, 李绍旦, 等. 补肾活血方对帕金森病模型小鼠TLR4/NF-κB信号通路的影响[J]. 中国中西医结合杂志, 2021, 41(3): 350-355.
Chen Y F, Luan Z X, Li S D, et al. Effect of Bushen Huoxue recipe on TLR4/NF-κB signal pathway in Parkinson's disease model mice[J]. Chin J Integr Tradit West Med, 2021, 41(3): 350-355.
[48]毕殿勇.阴虚动风证帕金森病模型大鼠黑质纹状体NF-κB介导的炎症反应及复方地黄颗粒的干预作用[D]. 上海: 上海中医药大学, 2020.
Bi D Y. Activation of NF-κ B signal pathway and intervention of Compound Rehmannia Granule in Parkinson's disease model rats of Endogeneous Wind Caused by YIN deficiency[D]. Shanghai: Shanghai University of Traditional Chinese Medicine,2020.
[49]韦晓芸, 胡玉英, 莫雪妮, 等. 胡玉英基于多靶点一细胞凋亡用真武汤合血府逐瘀汤辨治血水同病之帕金森病[J]. 内蒙古中医药, 2020, 39(2): 61-64.
Wei X Y, Hu Y Y, Mo X N, et al. Hu Yuying's Quito target-cell apoptosis treating PD of blood-water syndromes with Zhenwu decoction and Xuefu Zhuyu Decoction[J]. Nei Mongol J Tradit Chin Med, 2020, 39(2): 61-64.
[50]陈宝鑫, 赵世娇, 金香兰, 等. 健脾益肾通络方对MPTP诱导的帕金森病小鼠的保护作用及其机制[J]. 北京中医药, 2019, 38(7): 631-634.
Chen B X, Zhao S J, Jin X L, et al. Neuroprotective effect of Jianpi Yishen Tongluo Recipe on MPTP-induced Parkinson's disease in mice and its mechanism[J]. Beijing J Tradit Chin Med, 2019, 38(7): 631-634.
[51]祁羚, 汪瑶, 李亚楠, 等. 电针对鱼藤酮诱导的帕金森病大鼠神经炎性反应及Toll样受体4/核因子-κB信号通路的影响[J]. 针刺研究, 2021, 46(11): 929-934, 972.
Qi L, Wang Y, Li Y N, et al. Electroacupuncture improves behavioral activities by suppressing neuroinflammation and TLR 4/NF-κB signaling in substantia nigra of midbrain in Parkinson's disease rats[J]. Acupunct Res, 2021, 46(11): 929-934, 972.

基金资助

^*国家自然科学基金(82104793);湖南省自然科学基金医卫联合项目(2025JJ80936);湖南省自然科学基金高校联合项目(2026JJ81027);湖南省教育厅科学研究项目(25A0281);2024 年度大学本科生科研创新基金项目(2024BKS150);湖南中医药大学2024年大学生创新创业训练计划项目(X202410541176);湖南中医药大学2025年大学生创新创业训练计划(X202510541012)