中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2022, Vol. 17 ›› Issue (4): 773-774.doi: 10.4103/1673-5374.322451

• 观点:脑损伤修复保护与再生 • 上一篇    下一篇

集落刺激因子1：神经元的朋友还是敌人？

  

  • 出版日期:2022-04-15 发布日期:2021-10-16

Colony stimulating factor 1: friend or foe of neurons?

Lorna Bo, Xuenong Bo*   

  1. School of Clinical Medicine, University of Cambridge, Cambridge, UK (Bo L)
    Centre for Neuroscience, Surgery and Trauma, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK (Bo X)
  • Online:2022-04-15 Published:2021-10-16
  • Contact: Xuenong Bo, PhD, x.bo@qmul.ac.uk.
  • Supported by:
    The present work was supported by Foresight Inc. (to XB). No conflicts of interest exist between Foresight Inc. and publication of this work.

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摘要： Neural Regen Res：在中枢神经系统病理条件下增加集落刺激因子1释放的影响
    集落刺激因子1受体是一种酪氨酸激酶受体，主要表达于小胶质细胞和中枢神经系统的一小部分神经元上，直接控制小胶质细胞的稳态、活化和增殖。其配体包括集落刺激因子1和白细胞介素34，它们与集落刺激因子1受体的同一区域结合。这两种配体具有重叠的功能，但在信号转导方面也有一定的差异，并诱导不同的转录谱。集落刺激因子1和白细胞介素34通常由中枢神经系统的神经元表达，但集落刺激因子1也由星形胶质细胞表达。集落刺激因子最初的特点是能够触发骨髓前体细胞向成熟髓样细胞的分化，但后来发现它们也作用于成熟髓样细胞，包括小胶质细胞。在稳态脑中，集落刺激因子1的基线水平有助于维持小胶质细胞在突触修剪、神经营养因子释放和促进脑连接方面的作用。最新研究表明，在过去十年左右的时间里，小胶质细胞的慢性激活与神经退行性疾病的恶化有关，包括阿尔茨海默病、帕金森病、多发性硬化症和肌萎缩侧索硬化症。然而也有相反的研究表明，在其他情况下，活化的小胶质细胞是治疗性的，并可能减轻神经退行性变。通过集落刺激因子1受体和其他小胶质细胞受体（如TLRs、CX3CR1和嘌呤受体）激活小胶质细胞可诱导不同的表型，这取决于病变的类型和阶段，以及大脑的年龄，因为所有这些因子都进入细胞因子环境。
来自英国剑桥大学的Lorna Bo团队认为，促炎性M1表型是在促炎性细胞因子的存在下，通过刺激集落刺激因子1受体和其他受体诱导的，比如-淀粉样蛋白，脂多糖或髓鞘碎片，并有助于神经退行性变。抗炎M2表型是由集落刺激因子1受体和其他受体在存在抗炎细胞因子的情况下刺激产生的，并通过吞噬、增殖和再髓鞘化促进神经保护。在急性损伤时，小胶质细胞分化为M1表型以对抗损伤/感染，随后转变为M2样表型以实现组织修复。然而，在慢性神经退行性变过程中，更多的M1表型的小胶质细胞得以维持，从而使疾病恶化。尽管集落刺激因子1/集落刺激因子1受体在神经退行性变和神经保护作用方面的研究仍存在争议，但在许多神经退行性变模型中，阻断集落刺激因子1/集落刺激因子1受体系统具有神经保护作用。其机制可能是通过消除慢性激活的促炎性小胶质细胞。必须注意有关集落刺激因子1/集落刺激因子1受体神经保护作用的相互矛盾的证据，特别是在阿尔茨海默病模型和急性脑损伤中。未来使用不同疾病模型的研究应关注不同脑区、疾病进展阶段、脑年龄、细胞因子暴露等对集落刺激因子1/集落刺激因子1受体抑制的影响，这将有助于阐明小胶质细胞表型和功能的时空差异。进一步的研究还应致力于探讨白细胞介素-34的作用（如果有的话）以及集落刺激因子1对神经元的潜在直接影响。这些知识将有助于开展针对集落刺激因子1/集落刺激因子1受体通路的临床研究。   
   文章在《中国神经再生研究（英文版）》杂志2022年 4 月 4 期发表。

https://orcid.org/0000-0002-9202-3562 (Xuenong Bo) 

Abstract: Colony stimulating factor 1 receptor (CSF1R) is a tyrosine kinase receptor primarily expressed on microglia and a small subpopulation of neurons in the central nervous system (CNS), which directly controls the homeostasis, activation, and proliferation of microglia. Its ligands include CSF1 and interleukin-34 (IL-34), which bind to the same region of CSF1R. The two ligands have overlapping functions, however, they also have some differences in signal transduction and induce different transcription profiles. CSF1 and IL-34 are generally expressed by neurons in the CNS, but CSF1 is also expressed by astrocytes. The colony stimulating factors were first characterized by their ability to trigger the differentiation of bone marrow precursor cells into mature myeloid cells but were later found to also act on mature myeloid cells including microglia. In the homeostatic brain, a baseline level of CSF1 helps to maintain microglial roles of synaptic pruning, release of neurotrophic factors, and promotion of brain connectivity. However, over the past decade or so, chronic activation of microglia has been implicated in exacerbating neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease, multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS) (Xu et al., 2021). Yet there have also been studies in contradiction, which showed that in other circumstances, activated microglia were therapeutic and might mitigate neurodegeneration. So, is CSF1 the friend or foe of neurons?