Interaction between satellite glial cells and neurons in sensory neuropathic pain

doi:10.3969/j.issn.2095-4344.0587

Abstract

Abstract:

BACKGROUND: Although the studies on mechanism of neuropathic pain have made great progress, most of the studies focused on neurons, and little is known about satellite glial cells.
OBJECTIVE: To analyze the interaction between satellite glial cells and neurons in dorsal root ganglion in sensory neuropathic pain.
METHODS: A computer-based search of PubMed, SinoMed, and other databases was conducted to retrieve literature addressing satellite glial cells, sensory neurons, dorsal root ganglia, and neuropathic pain. The keywords were “satellite glial cells, sensory neurons, dorsal root ganglion, neuropathic pain” in English and Chinese, respectively. Finally 61 eligible studies were included.
RESULTS AND CONCLUSION: Satellite glial cells and neurons form an independent functional unit. Between them, information is transmitted through gap links, neurotransmitters, and ion channels. Satellite glial cells take glutamic acid to maintain the extracellular level of glutamic acid, thereby maintaining the excitement of neurons. Satellite glial cells play an important role in the maintenance and development of neuropathic pain, and Fractalkine is an important factor in pain development. Therefore, inhibiting fractalkine/CX3CR1 signal transduction in satellite glial cells is the treatment target.

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

Key words: Neurons, Sensation, Ganglia, Spinal Cord, Neuragia, Tissue Engineering

CLC Number:

R446

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R446

Wang Xianbin, Li Liyan. Interaction between satellite glial cells and neurons in sensory neuropathic pain[J]. Chinese Journal of Tissue Engineering Research, 2019, 23(11): 1788-1793.

Figures/Tables 2

2.1 背根节神经节的解剖结构背根神经节位于脊柱两椎骨之间，向中枢连接脊髓前角和后角神经元，其向外周沿神经纤维接受躯体感觉信号和输出中枢运动控制信号。在背根节中主要由感觉神经元、卫星胶质细胞以及许旺细胞组成。卫星胶质细胞包绕在感觉神经元胞体周围，与神经元共同组成了一个功能相对独立的结构单位[16]。 2.2 卫星胶质细胞在维持神经元外环境的静息状态中的作用 2.2.1 缝隙连接是几乎存在于所有动物的细胞膜上，是细胞间进行直接交流的唯一信息通道。缝隙连接的通道可让部分小分子通过从而进入另一个细胞实现代谢偶联或电偶联，如细胞内的无机盐离子、氨基酸、三磷酸腺苷等小分子物质[17]。缝隙连接广泛存在，两种同类型的细胞间或者不同类型的细胞间均存在缝隙连接。例如，在中枢神经系统中，缝隙连接就存在于神经元之间、胶质细胞之间以及神经元与胶质细胞之间[18]。在外周神经系统同样有类似的缝隙连接存在，在神经冲动信息传递及各种反应过程中，通过缝隙连接调节细胞外离子浓度，神经元与神经胶质细胞间的电活动等作用，维持着细胞内外环境的稳定和信息交流的功能[19-20]。缝隙连接的基础是缝隙连接蛋白[21]，在神经元上的连接蛋白主要是Cx26、Cx32和Cx36，而星形胶质细胞和卫星胶质细胞表面主要是Cx43[18]。神经病理性疼痛大部分是由于外周神经损伤导致，外周神经损伤后将导致痛觉过敏，是由于增强了感觉神经元的兴奋性，降低了神经元的兴奋阈值。神经损伤后，卫星胶质细胞也可能在脊髓伤害信号的传递中发挥重要作用[14]。研究表明，胶质细胞间的缝隙连接可能在神经病理性疼痛中发挥重要作用[15]。当神经损伤后，卫星胶质细胞间的缝隙连接数目明显增多[22]。卫星胶质细胞间缝隙连接数量在神经受损后将会明显增多，但过一段时间后又逐渐恢复到正常水平，然而神经受损导致的神经病理性疼痛并未痊愈，因此神经病理性疼痛的发生发展机制不仅仅只有缝隙连接发挥作用。 2.2.2 离子通道和神经递质神经损伤后，损伤部位大量的炎性细胞聚集释放炎性递质，使化学信号诱发产生电信号传递到背根节或三叉神经节，电信号在背根节或三叉神经节转换。研究证明，ATP是参与神经元与卫星胶质细胞通讯的主要信号传送者之一[23]，当神经冲动到达背根节时，卫星胶质细胞和神经元会大量释放ATP，从而激活嘌呤能(P2)受体(例如P2X和P2Y)，增加细胞间钙离子浓度[24-27]。嘌呤能受体P2Y12 R的激活，可增加卫星胶质细胞的钙离子内流，反过来增加细胞的兴奋性[28-30]。背根节中，细胞间存在大量的离子以维持细胞电位的稳定，神经节中的卫星胶质细胞在钾离子缓冲中起着重要作用[31]。细胞间钾离子的稳态维持着神经元的兴奋性，当细胞外钾离子浓度增加时，神经元兴奋性增加[32]。卫星胶质细胞表达内向整流钾通道Kir4.1，其缓冲神经节中的钾浓度[31]。研究表明，当神经损伤后，Kir4.1的表达下调，并且siRNA沉默Kir4.1在自由移动的大鼠中诱导自发和诱发的面部疼痛样行为，见图1[33]。"

神经损伤后，电信号传递到神经节中，导致神经元大量释放神经递质以及神经和免疫因子，如谷氨酸，ATP，P物质，CGRP，脑源性神经营养因子，白细胞介素6和CCL2等[34-36]。这些介质增加突触后神经元的敏感性，并激活神经元周围的卫星胶质细胞。外周释放的免疫因子，如促炎性细胞因子(如白细胞介素6)也可能激活中枢神经胶质细胞[37-38]。外周白细胞介素6可通过循环转运到中枢神经系统，增加大脑血管内皮细胞中的COX-2活性和PGE2的释放，从而导致中枢免疫应答[37-38]。 2.2.3 卫星胶质细胞谷氨酸-谷氨酰胺循环调节神经元活动谷氨酸是中枢神经和外周神经系统中重要的兴奋性神经递质，过多的谷氨酸会导致神经元的兴奋性增加，从而导致疼痛。卫星胶质细胞摄取细胞外谷氨酸，维持神经元外谷氨酸的稳态平衡。胶质细胞和神经元之间的谷氨酸-谷氨酰胺循环在增加神经损伤后的神经元兴奋性方面也起着关键作用[39-41]。胶质细胞摄取已经释放到突触中的谷氨酸，然后谷氨酰胺合成酶将其合成谷氨酰胺。神经元使用谷氨酰胺生产谷氨酸，补充谷氨酸供应[39-41]。谷氨酸转运蛋白GLT-1参与谷氨酸转运入胶质细胞。神经损伤后，GLT-1下调，导致谷氨酸积累，从而增加突触后神经元的兴奋性[42]。研究表明，病理性疼痛大鼠模型中，感觉神经元胞体中的谷氨酸含量增加[43]。在外周神经系统中并不含有降解谷氨酸的酶，所以谷氨酸的清除主要依靠卫星胶质细胞上高亲和力的谷氨酸转运体来进行。卫星胶质细胞上也表达谷氨酸的运载体谷氨酸-天冬氨酸受体(glutamate-aspartate transporter，GLAST) 和谷氨酰胺合成酶(glutamine synthetase，GS)，因此，卫星胶质细胞可以摄取细胞外的谷氨酸，并且在细胞内将谷氨酸合成谷氨酰胺。卫星胶质细胞摄取谷氨酸的作用可以维持细胞外谷氨酸的正常水平，从而维持神经元的兴奋性[44]。 2.2.4 卫星胶质细胞促进交感芽生以调节神经元活动 1993年，McLachlan和Chung分别报道在神经病理性疼痛模型建立后，背根神经节内的交感神经轴突(酪氨酸羟化酶阳性，THIR)末梢出芽增生并在一些大中直径胞体感觉神经元周围形成所谓“篮状结构(basket structure)”[45-46]。交感发芽和神经病理疼痛的机制主要有直接耦联和间接耦联两种假说[47]，但这两种假说都忽视了背根节中的胶质细胞，现研究发现胶质细胞在交感芽生从而导致神经病理性疼痛的过程中可能起着至关重要的作用[48]。有研究发现，在电镜下交感轴突在卫星细胞层形成的曲张体结构，这些交感轴突末梢与卫星胶质细胞间可以形成类似突触的结构，猜测卫星胶质细胞与感觉神经元之间可能存在交感-感觉偶联，从而起着中介的作用[49]。此外，有研究发现，卫星胶质释放的神经营养因子能够促进交感出芽结构的形成，如神经生长因子，NT-3，脑源性神经营养因子等[50-51]。神经损伤后,背根节中的卫星胶质细胞神经生长因子 mRNA表达明显升高，且背根神经节中神经元并不能合成神经生长因子，用神经生长因子抗体干预后发现交感芽生明显减少[52]。此外，在神经病理性疼痛模型鞘内给予神经生长因子，背根节中有大量交感出芽和篮状结构形成[53]，外周神经损伤后，背根节中卫星胶质细胞释放神经生长因子或NT-3，启动了交感轴突的再生过程，使得交感轴突向卫星细胞发芽，与卫星胶质细胞形成交感-感觉偶联，从而调节神经元的活动[34]。 2.2.5 趋化因子介导背根神经节神经元与卫星胶质细胞的相互作用趋化因子是指一类低分子量的蛋白质，因其趋化细胞的迁移而得名[54]。在神经系统中，趋化因子发挥着重要的作用，参与各种生物学过程，包括控制免疫细胞趋化，刺激新血管形成、刺激释放炎症细胞因子、调节细胞间信息传递等[55]。Fractalkine是一种与神经元细胞外表面相连的独特趋化因子，见表1。"

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