The CX3CL1-CX3CR1 Axis Regulates Microglia-Neuron Interactions and Its Role in Neurological Disorders
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摘要: 小胶质细胞是中枢神经系统的常驻免疫细胞，参与炎症调节、突触修剪、吞噬清除和神经营养支持等。神经元细胞表达的C-X3-C基序趋化因子配体1（C-X3-C motif chemokine ligand 1，CX3CL1）与小胶质细胞表面的C-X3-C基序趋化因子受体1（C-X3-C motif chemokine receptor 1，CX3CR1）共同构成调节两者间相互作用的重要信号系统。CX3CR1表达变化或功能改变可影响小胶质细胞的迁移、炎症反应、吞噬和突触修剪等效应，进而影响神经元存活、突触结构及神经网络功能。既往研究显示，该信号系统异常与孤独症谱系障碍、神经退行性疾病、脑缺血、低氧相关认知损伤和癫痫等疾病的发生和进展相关，且该信号系统受疾病类型、脑区及病程阶段等因素影响。围绕CX3CR1变化，综述神经元和小胶质细胞CX3CL1-CX3CR1信号系统的基本特征、相互作用机制及其在神经系统疾病中的变化，为进一步认识CX3CR1的病理作用和潜在干预价值提供参考。Abstract: Microglia are resident immune cells of the central nervous system, participating in inflammatory regulation, synaptic pruning, phagocytic clearance, and neurotrophic support. C-X3-C motif chemokine ligand 1 （CX3CL1） expressed by neurons and C-X3-C motif chemokine receptor 1 （CX3CR1） on the surface of microglia together constitute an important signaling system that regulates the interactions between the two cell types. Alterations in CX3CR1 expression or function can affect microglial migration, inflammatory responses, phagocytosis, and synaptic pruning, thereby influencing neuronal survival, synaptic structure, and neural network function. Previous studies have shown that abnormalities in this signaling system are associated with the onset and progression of disorders such as autism spectrum disorder, neurodegenerative diseases, cerebral ischemia, hypoxia-related cognitive impairment, and epilepsy, and that this signaling system is influenced by factors including disease type, brain region, and disease stage. Focusing on changes in CX3CR1, this review summarizes the basic characteristics of the neuronal-microglial CX3CL1-CX3CR1 signaling system, the mechanisms underlying their interactions, and its alterations in neurological diseases, with the aim of providing a reference for better understanding the pathological roles of CX3CR1 and its potential value as a therapeutic target.
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Key words:
- CX3CR1 /
- CX3CL1 /
- Microglia /
- Neurons /
- Neuroinflammation /
- Neurological diseases
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图 1 CX3CL1-CX3CR1信号调控小胶质细胞与神经元相互作用的机制
Figure 1. Mechanisms by which CX3CL1-CX3CR1 signaling regulates microglia-neuron interactions
图 2 CX3CR1信号异常在疾病中的双面作用模式图
Figure 2. Dual roles of dysregulated CX3CR1 signaling in disease
表 1 不同神经相关疾病中CX3CR1变化及小胶质细胞–神经元结局汇总
Table 1. Alterations in CX3CR1 and microglia–neuron outcomes across different neurologically related diseases
疾病分类 模型类型 CX3CR1变化方向 小胶质细胞表型 神经元结局 参考文献 孤独症谱系障碍 Cx3cr1敲除小鼠（发育期） CX3CR1缺失 小胶质细胞数量暂时减少，突触募集与吞噬/修剪延迟 树突棘密度升高，突触传递与脑网络成熟异常 [19] 孤独症谱系障碍 Cx3cr1敲除小鼠 CX3CR1缺失 神经元—小胶质细胞信号交流受损 功能连接减弱，社会交往减少并出现重复行为 [29] 孤独症谱系障碍 人群遗传学及细胞功能实验 Ala55Thr罕见变异；功能降低 CX3CL1诱导的Akt磷酸化减弱，细胞应答受损 与孤独症谱系障碍表型风险相关，但变异罕见 [30] 孤独症谱系障碍 孕期丙戊酸暴露大鼠 海马CX3CR1及CX3CL1无明显变化 未发现可归因于该信号轴的明确改变 未支持CX3CR1改变是该模型的共同特征 [31] 阿尔茨海默病 淀粉样蛋白驱动的小鼠模型/Cx3cr1缺失 CX3CR1缺失 与Aβ斑块接触减少，Aβ吞噬及溶酶体酸化受损，炎症和氧化反应异常 Aβ负荷及Tau磷酸化增加，突触后结构和神经元减少，工作记忆恶化 [35] 阿尔茨海默病 Tau摄取实验及Cx3cr1缺失模型 CX3CR1缺失或减少 小胶质细胞对细胞外Tau的内化能力下降 Tau清除受损，可能促进Tau病理积累 [36] 阿尔茨海默病 晚发性阿尔茨海默病人群 CX3CR1-V249I功能变异 未直接评价小胶质细胞表型 与神经原纤维病理进展相关 [37] 帕金森病 α-突触核蛋白A53T小鼠/Cx3cr1缺失 CX3CR1缺失 小胶质细胞活化及神经炎症增强 黑质多巴胺能神经元丢失加重 [38] 肌萎缩侧索硬化症 SOD1G93A小鼠/Cx3cr1缺失 CX3CR1缺失 小胶质细胞活化增强，异常SOD1聚集增加 运动神经元丢失及终末期疾病表现加重 [39] 肌萎缩侧索硬化症 SOD1G93A小鼠（症状期） CX3CL1降低、CX3CR1升高 促炎反应增强；受体升高可能为代偿性变化 运动神经元减少 [40] 脑缺血/脑卒中 实验性缺血性脑卒中小鼠/Cx3cr1信号缺失 CX3CR1信号缺失 小胶质细胞焦亡及炎症反应受到抑制 卒中后认知功能恢复改善 [42] 脑缺血/脑卒中 脑缺血模型及神经元培养 缺血诱导神经元CX3CR1升高 该研究重点为神经元CX3CR1，未直接界定小胶质细胞表型 CX3CR1介导Ca2+内流和兴奋性毒性；敲除或中和后神经元死亡减少 [43] 脑缺血/脑卒中 全脑缺血及低氧后处理小鼠 胶质细胞CX3CR1降低；CX3CL1相关保护信号并存 海马CA1区小胶质细胞活化及TNF-α、IL-1β表达减少 CA1神经元存活增加；作用具有细胞来源和时相差异 [44] 低氧相关认知损伤 高海拔/低压低氧暴露小鼠及体外低氧模型 CX3CL1-CX3CR1信号增强 CD16、IL-1β表达及海马CA1突触吞噬增加；Cx3cr1缺失可减轻上述改变 PSD95等突触成分减少、突触丢失并出现记忆损害 [45] 癫痫 海人酸诱导癫痫持续状态；CX3CR1拮抗剂AZD8797干预 发作后CX3CR1相关信号增强；药理性抑制 拮抗CX3CR1后小胶质细胞活化及炎症反应减轻 海马神经元损伤减轻；作用可能随发作后阶段变化 [46] 注：CX3CR1表达变化不等同于受体功能变化；同一疾病中的作用可随模型、受累细胞、脑区及病程阶段而改变。Aβ，淀粉样β蛋白；ROS，活性氧。 
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