趋化因子及其受体在认知障碍性疾病中的研究进展

赵后雨 , 梁坤 , 于泽源 , 丁伟 , 文宇坤 , 黄建铭 , 方以群

重庆医科大学学报 ›› 2025, Vol. 50 ›› Issue (07) : 920 -925.

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重庆医科大学学报 ›› 2025, Vol. 50 ›› Issue (07) : 920 -925. DOI: 10.13406/j.cnki.cyxb.003735
脑科学与神经精神系统疾病前沿

趋化因子及其受体在认知障碍性疾病中的研究进展

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Research advances in chemokines and their receptors in cognitive disorders

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摘要

认知障碍是很多神经系统疾病如脑卒中、多发性硬化、神经退行性疾病等的主要临床表现,神经炎症是认知障碍性疾病发生最重要的机制之一。趋化因子是一类高度保守的小分子分泌蛋白,它们与位于细胞膜上的相应的趋化因子受体结合,激活下游的信号通路,在细胞的移动、增殖、分化和存活中发挥重要作用。在中枢神经系统中,趋化因子及其受体参与免疫反应,对神经炎症具有一定的调控作用。本文将对趋化因子及其受体在认知障碍性疾病中的研究进展进行详细综述,以期为相关疾病的早期诊断及治疗提供新思路和新靶点。

Abstract

Cognitive impairment is the main clinical manifestation of many nervous system diseases such as stroke,multiple sclerosis,and neurodegeneration,and neuroinflammation is one of the key mechanisms for the onset of cognitive disorders. Chemokines are a class of highly conserved small-molecule secretory proteins that bind to the corresponding chemokine receptors located on cell membrane,activating downstream signaling pathways and playing an important role in cell migration,proliferation,differentiation,and survival. In the central nervous system,chemokines and their receptors are involved in immune response and can exert a certain regulatory effect on neuroinflammation. This article reviews the research advances in chemokines and their receptors in cognitive disorders,in order to provide new insights and targets for the early diagnosis and treatment of related diseases.

关键词

趋化因子 / 趋化因子受体 / 神经炎症 / 认知障碍 / 认知障碍性疾病

Key words

chemokines / chemokine receptors / neuroinflammation / cognitive impairment / cognitive disorders

引用本文

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赵后雨,梁坤,于泽源,丁伟,文宇坤,黄建铭,方以群. 趋化因子及其受体在认知障碍性疾病中的研究进展[J]. 重庆医科大学学报, 2025, 50(07): 920-925 DOI:10.13406/j.cnki.cyxb.003735

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趋化因子(chemokines)是一类小蛋白,通常由70~80个氨基酸残基组成。根据氨基酸序列中半胱氨酸的位置,趋化因子可分为CCL、CXCL、CX3CL和XCL 4个亚家族[1-2]。除CXCL16和CX3CL1外,其他趋化因子均为分泌蛋白。趋化因子通过与糖胺聚糖相互作用被固定在细胞外基质或细胞膜上,调节单核细胞/巨噬细胞和淋巴细胞的聚集和迁移[3]。趋化因子受体属于G蛋白偶联受体(G-protein coupled receptors,GPCRs),共20个受体,包括7个CXC受体、10个CC受体、CX3CR1和2个XCR1。趋化因子与受体结合后,通过G蛋白变构将细胞外信号传导至细胞内,触发细胞内信号通路,参与细胞活化和运动[4]。趋化因子及其受体在肿瘤、获得性免疫缺陷综合症(acquired immune deficiency syndrome,AIDS)、过敏性疾病及COVID-19等多种疾病中发挥作用,且与神经炎症及中枢神经系统的发育和功能密切相关。认知障碍性疾病主要特征是认知功能的显著下降,影响记忆、语言、注意力、执行功能和视觉空间能力等多个方面,严重影响人类健康和生活质量。多种疾病如神经退行性疾病、缺血性疾病、神经炎症性疾病等均可出现认知障碍的表现。越来越多的研究表明,趋化因子及其受体在上述疾病的发生发展过程中也起重要作用。本文综述了趋化因子及其受体在认知障碍性疾病中的研究进展,旨在为该类疾病的发病机制及防治研究提供理论依据。
认知障碍性疾病中研究较多的趋化因子及其受体主要有趋化因子CCL11(c-c motif ligand 11,CCL11)/C-C趋化因子受体3型(c-c chemokine receptor type 3,CCR3),C-C趋化因子配体2(c-c chemokine ligand 2,CCL2)/C-C趋化因子受体2型(c-c chemokine receptor type 2,CCR2),C-C趋化因子配体5(c-c chemokine ligand 5,CCL5)/C-C趋化因子受体5型(c-c chemokine receptor type 5,CCR5),C-X-C趋化因子配体10(c-x-c motif chemokine ligand 10,CXCL10)/C-X-C趋化因子受体3型(c-x-c chemokine receptor type 3,CXCR3),C-X3-C趋化因子配体1(c-x3-c motif chemokine ligand 1,CX3CL1)/C-X3-C趋化因子受体1型(c-x3-c chemokine receptor 1,CX3CR1),C-X-C趋化因子配体1(c-x-c motif chemokine ligand 1,CXCL1)/C-X-C趋化因子受体2型(c-x-c chemokine receptor type 2,CXCR2),下面将进行一一介绍。

1 趋化因子及其受体与在认知障碍性疾病中的作用

1.1 CCL11/CCR3

CCL11被称为“嗜酸性粒细胞趋化因子1型(eotaxin-1)”,既可从血液中透过血脑屏障直接运输到大脑,也可由中枢神经系统中的小胶质细胞直接合成。有证据表明CCL11与衰老和神经发生减少有关,因此被称为“内源性认知退化趋化因子”或“大脑衰老加速趋化因子”。给年轻小鼠注射重组CCL11蛋白会引起认知障碍,而在衰老大鼠中使用CCL11中和抗体会明显改善其认知障碍[5]。在引起认知障碍的多发性硬化症(multiple sclerosis,MS)[6]、阿尔茨海默病(Alzheimer’s disease,AD)和重度抑郁症、躁狂症和精神分裂症等神经精神疾病[7-8]中都检测到了CCL11水平的升高。此外,最近的实验还发现COVID-19感染患者脑脊液中的CCL11水平明显增加,且升高水平与患者的认知障碍程度相关[9-10]。CCR3是CCL11的主要受体,在中枢神经系统中,CCR3在小胶质细胞、神经元和星形胶质细胞上表达[11]。CCL11激活CCR3后既可以通过介导神经炎症反应导致认知损伤,也可直接诱导Aβ产生、tau蛋白过度磷酸化和树突棘丧失引起认知障碍。1项研究发现,在APP/PS1双转基因小鼠体内敲除CCR3,会显著减轻细胞周期蛋白依赖性激酶 5(cyclin-dependent kinase 5,CDK5)和糖原合酶激酶-3β(glycogen synthase kinase 3 beta,GSK3β)磷酸化、tau蛋白过度磷酸化、Aβ沉积、小胶质细胞增生、星形胶质细胞增生、突触丧失等病理变化,导致小鼠空间学习和记忆能力的下降[12]。另外,该项研究还发现CCL11处理的原代神经元会导致CDK5和GSK3β的磷酸化,而CCR3特异性拮抗剂可阻断这些效应[12]。CCR3抑制剂对CCL11诱导的学习记忆障碍的改善作用在其它研究中也得到了证实[13]

综上所述,CCL11/CCR3在认知障碍性疾病的发病机制中扮演着重要角色。CCL11/CCR3与神经炎症反应相关,并可能通过多种途径对认知功能产生不利影响。诸多研究表明,利用CCL11中和抗体和CCR3抑制剂抑制CCL11/CCR3信号转导可能成为治疗认知障碍性疾病的潜在策略。然而,尽管CCL11/CCR3在认知障碍性疾病中的作用已经得到初步证实,但还有很多挑战和未解之谜需要进一步研究。例如,需要更好地理解CCL11/CCR3的调控机制、与其他炎症因子的相互作用以及在不同认知障碍性疾病中的特异性表达模式。此外,还需要深入研究CCL11/CCR3作为潜在生物标志物的可行性,以便将其应用于认知障碍性疾病的早期诊断和治疗监测。

1.2 CCL2/CCR2

CCL2又称单核细胞趋化蛋白1(monocyte chemoattractant protein-1,MCP-1),是一种强效趋化因子,可促进巨噬细胞、单核细胞、活化T细胞和NK细胞向中枢神经系统的趋化[14]。在中枢神经系统中,CCL2主要由小胶质细胞产生,是小胶质细胞激活和神经炎症发生的关键趋化因子[15]。研究表明,CCL2是Aβ刺激小胶质细胞和星形胶质细胞产生神经炎症反应的重要组成部分[16]。CCL2的受体是CCR2,CCR2由单核细胞和T淋巴细胞表达,是调节单核细胞和巨噬细胞迁移和浸润的最有效的趋化因子,CCL2/CCR2结合后可促进单核细胞和巨噬细胞分泌TNF-α、IL-1β和IL-6等促炎因子,促进炎症反应。在多发性硬化[17-18]、脑卒中和AD[19-20]等疾病的发生发展过程中均检测到CCL2/CCR2的上调。CCL2/CCR2也参与很多其他原因导致的认知障碍,例如乙醇诱导的认知障碍[21]、糖尿病相关认知障碍[22]、抑郁症相关认知障碍等[22]。另外1 项研究发现持续的军事行动可能会通过疲劳、焦虑、应激反应等导致认知功能障碍,军事人员认知障碍的程度与血清中CCL2的浓度相关[23]。CCL2/CCR2为认知障碍性疾病的干预与治疗提供了新的靶点,抑制或阻断CCL2/CCR2可以缓解患者的认知功能减退在多项研究中已得到证实。CCL2抑制剂Bindarit和CCR2拮抗剂RS04393可抑制乙醇诱导的神经炎症与神经功能损伤[21]。CCL2抑制剂DAPTA可通过下调炎症介质和阻断NF-κB/Notch信号传导,减轻MS导致的认知障碍症状[24]。拮抗CCR2可以改善癫痫引起的多种病理变化,包括血脑屏障的破坏、小胶质细胞的增生及神经元的损伤,改善癫痫引起的认知功能障碍[25]。在脓毒症时针对CCR2+炎症单核细胞进行治疗可以提供一种新型的神经保护性干预措施,以预防认知障碍的发生发展[26]。此外,研究发现,AD患者脑脊液中CCL2的水平与认知障碍的严重程度明显相关,可作为AD进展的生物学指标[27]。脑小血管病继发血管性痴呆患者血清中的CCL2水平升高,且升高水平对血管性痴呆具有一定的诊断价值,可作为预测该病的重要指示剂[28]

总的来说,CCL2/CCR2信号通路在多种认知障碍性疾病的发生发展中发挥重要作用,CCL2/CCR2的异常增加与炎症反应、神经元损伤和认知功能下降密切相关。CCL2/CCR2信号通路也为很多认知障碍性疾病的治疗提供了新的靶点,研究结果表明通过干预CCL2/CCR2可以减轻神经炎症反应、改善神经元功能并最终缓解认知障碍性疾病。此外,CCL2可能有望成为反映认知障碍严重程度的潜在生物标志物,值得深入研究。

1.3 CCL5/CCR5

CCL5也称RANTES,是M1巨噬细胞的标记,主要由活化的T细胞、单核细胞、巨噬细胞等分泌。在中枢神经系统中,CCL5主要由星形胶质细胞分泌,但小胶质细胞和神经元也会分泌这种趋化因子。CCL5与其受体CCR5结合后,具有很强的单核细胞趋化作用[29]。CCL5/CCR5参与神经炎症反应的发生,1项研究发现,应激介导的CCL5/CCR5轴失调会引发小胶质细胞对突触和神经血管成分的过度吞噬,从而导致神经炎症反应、神经传递障碍、血脑屏障受损及应激敏感性增加[30]。此外,CCR5是人类免疫缺陷病毒(human immunodeficiency virus,HIV)进入免疫细胞的主要共受体,它在中枢神经系统中的表达会促进神经炎症的发生,引起认知障碍,CCR5拮抗剂Maraviroc可以改善HIV相关认知障碍[31]。CCL5/CCR5与AD密切相关,Aβ和tau蛋白表达增加是AD的典型病理变化,在AD患者与小鼠模型中均发现了CCL5的显著上调,且CCL5的上调水平与Aβ和tau水平呈正相关[32]。CCL5/CCR5还可通过激活PI3K-AKT-mTORC1轴,引起mTORC1上调及自噬紊乱,导致毒性蛋白质的累积,引发神经认知障碍,而CCR5的药理学或遗传抑制可以逆转这些变化[33]

综上所述,CCL5/CCR5在认知障碍性疾病中的研究进展表明,它与神经炎症反应、神经退行性变、神经元的迁移和突触可塑性等有关。此外,还有研究发现CCL5/CCR5可以调控神经干细胞的增殖与分化,其异常表达与认知障碍症状的发生和发展密切相关。CCL5/CCR5的进一步研究可为认知障碍性疾病的预防和治疗提供新的靶点。

1.4 CXCL10/CXCR3

CXCL10被称为γ干扰素诱导蛋白10,可由单核细胞、内皮细胞、自然杀伤细胞等分泌,在中枢神经系统中,CXCL10主要由星形胶质细胞分泌。CXCL10的异常表达与认知障碍性疾病密切相关,颗粒体蛋白前体相关的前额颞叶退化症[34]、AD和轻度认知障碍患者[35]、帕金森认知障碍[36]患者均检测到了CXCL10水平明显升高。CXCL10的受体是CXCR3,在中枢神经系统中,CXCR3可由星形胶质细胞、小胶质细胞和神经元表达。研究发现在AD患者的脑内,神经元高表达CXCR3,星形胶质细胞分泌的CXCL10增多[37]。1项AD病理学的研究开发了包括干细胞源性神经元、星形胶质细胞和小胶质细胞以及外周免疫细胞的三维人类神经免疫轴模型,发现CXCL10/CXCR3在调节AD培养体系中T细胞的浸润及神经元损伤中发挥重要作用[38]。在TAR DNA结合蛋白43(tar dna-binding protein 43,TDP-43)诱导的痴呆小鼠模型中,发现海马体中干扰素诱导的星形胶质细胞表达CXCL10的显著升高,另外在海马神经细胞突触前末梢中也检测到CXCR3的增加[39]。在AD小鼠模型中,CXCL10激活CXCR3后抑制小胶质细胞的吞噬作用促进Aβ斑块的形成,从而导致认知障碍,而抑制或敲除CXCR3可改善APP/PS1模型小鼠的认知功能减退[40]。此外,研究发现,CXCR3抑制剂可增加小胶质细胞对Aβ的吞噬作用,减少小胶质细胞的激活,并抑制促炎细胞因子的释放[41-42],表明CXCR3可能成为认知障碍性疾病的潜在干预靶点。

综上所述,CXCL10/CXCR3在认知障碍性疾病研究中的进展表明,它在神经胶质细胞激活、神经炎症反应和神经元损伤等方面发挥重要作用,CXCL10/CXCR3的异常激活会促进认知障碍性疾病的发生。

1.5 CX3CL1/CX3CR1

CX3CL1是少数能在脑中持续表达的趋化因子之一,在中枢神经系统中主要表达于神经元和小胶质细胞[43]。CX3CL1的受体CX3CR1仅在中枢神经系统的小胶质细胞上表达,是一种“吃我”信号相关蛋白,负责突触消除[44]。CX3CL1与CX3CR1结合后导致神经损伤或神经保护作用仍存在很大争议。CX3CR1调节肌动蛋白重排和小胶质细胞的迁移,有助于突触重塑[45]。CX3CL1/CX3CR1信号传导与正常大脑发育过程中树突棘和小胶质细胞修剪有关,CX3CR1的下调会改变小胶质细胞的突触修剪并增加齿状回中的棘,在缺乏CX3CR1的小鼠脑中发现了更多的棘和不成熟的突触[46]。最近的1项研究发现,睡眠剥夺会下调CX3CR1,损害CX3CR1介导的突触修剪,对学习和记忆能力产生损害[47]。近期的1项研究发现大脑中动脉闭塞小鼠模型CX3CL1表达下调,外源性补充重组CX3CL1蛋白可抑制小胶质细胞中的细胞焦亡,减少NLRP3炎性小体和NF-κB信号传导的激活,抑制炎症因子的释放,明显改善小鼠的神经认知功能缺损[48]。以上研究结果指向的是CX3CL1/CX3CR1的神经保护作用,但是也有研究发现CX3CL1/CX3CR1的异常表达会造成神经损伤。血清中CX3CL1/CX3CR1的浓度与脑梗死患者梗死体积成正比,表明CX3CL1/CX3CR1信号轴与脑梗死病情密切相关,机制可能与CX3CL1大量分泌入血,促进炎性细胞因子的释放和内皮细胞的粘附有关[49]。抑制CX3CL1/CX3CR1可降低促炎细胞因子的表达,减少炎性损伤并提供神经保护[50-51]。此外,CX3CR1还可调节钙离子内流介导的神经元损伤,敲除小鼠神经元中的CX3CR1能够降低谷氨酸介导的神经元钙离子的内流速度和总量,明显减轻谷氨酸的兴奋性毒性,增加细胞存活率,对神经元起到保护作用[52]

综上所述,CX3CL1/CX3CR1在中枢神经系统内的作用较为复杂,CX3CL1与CX3CR1结合后一方面会促进促炎因子的释放造成更大的损伤,另一方面又可以趋化免疫细胞释放抗炎因子,起到神经保护作用。而且CX3CL1/CX3CR1在神经元的存活及突触可塑性中的作用也有两面性,其在认知障碍性疾病的具体作用机制仍需要进一步研究。

1.6 CXCL1/CXCR2

CXCL1主要表达于星形胶质细胞及皮层受损区域[53]。CXCL1通过与其受体CXCR2结合发挥生物学效应。正常状态下,在中枢神经系统中,CXCR2主要表达于神经元,脑损伤情况下,CXCR2高度表达于激活的小胶质细胞[54]。CXCL1/CXCR2可通过激活NLRP3,促进新生大鼠小胶质细胞的活化[55]和促炎细胞因子的释放[56],导致神经炎症反应的发生。脑创伤的患者和动物模型的大脑皮质中均发现了CXCR2表达水平的升高,过度表达的CXCR2可通过驱动外周单核细胞向脑脊液趋化,促进单核细胞介导的神经细胞免疫原性细胞死亡过程,破坏神经功能[57-58]。研究表明,CXCR2的特异性抑制剂SB332235可有效阻断CXCL1/CXCR2介导的激活的星形胶质细胞与小胶质细胞之间的相互作用,减少小胶质细胞的激活,减轻炎症反应,发挥神经保护效应[59-60]。此外,SB332235还可减轻神经元的退化和凋亡,缓解创伤性脑损伤诱导的运动和认知功能障碍[58]

综上所述,CXCL1/CXCR2在认知障碍性疾病研究中的进展表明,其异常表达会促进小胶质细胞的激活,引起神经炎症反应及神经元损伤。对CXCL1/CXCR2的深入研究将为认知障碍性疾病的干预提供了新靶点。

除了上述趋化因子/趋化因子受体外,研究发现其他趋化因子也参与认知障碍性疾病的发生与发展。例如,C-X-C趋化因子配体12(c-x-c motif chemokine ligand 12,CXCL12)介导单核细胞募集到血管周围,导致神经炎症并由此产生认知障碍[61]。C-C趋化因子配体3(c-c motif chemokine ligand 3,CCL3)和C-C趋化因子配体4(c-c motif chemokine ligand 4,CCL4)的水平在脑卒中患者中显著增加[62]。CXCL16/CXCR6也通过促进炎症反应、影响神经元发育与突触可塑性等导致认知障碍[63]。这些结果进一步支持了趋化因子在认知障碍性疾病中的重要作用。

2 总结与展望

本文综述了一些与神经认知症状密切相关的趋化因子及其受体,主要包括CCL11/CCR3,CCL2/CCR2,CCL5/CCR5,CXCL10/CXCR3,CX3CL1/CX3CR1,CXCL1/CXCR2等。越来越多的证据表明,趋化因子及其受体的结合在认知障碍性疾病的发生和发展中发挥重要作用。趋化因子及其受体通过介导神经炎症反应、影响自噬、神经细胞发育、神经递质传递、神经内分泌活动等过程影响神经认知功能。然而,在认知障碍性疾病的发生发展过程中,并非只有某一种趋化因子及其受体发生变化,而是多种趋化因子及其受体网络的变化。例如,在1 项临床研究中,脓毒症患者脑部的星形胶质细胞和巨噬细胞(CD68/CD45)被激活,CXCL8/10/12、CCL13/22水平均升高[64]

趋化因子及其受体在多种认知障碍性疾病中发挥重要作用,为干预和治疗提供了潜在的靶点。基础研究发现,部分趋化因子及受体的抑制剂或阻滞剂可减轻神经炎症、改善认知功能。认知障碍性疾病中趋化因子水平的显著变化提示这些因子有望成为关键分子标志物。未来的研究可通过单细胞转录组测序技术检测趋化因子及其受体在中枢神经系统中的表达,进一步揭示其与神经炎症、神经发育及功能的联系,阐明其在认知障碍中的机制。尽管趋化因子受体拮抗剂在基础研究中对认知障碍有显著改善,但尚未应用于临床。趋化因子及其受体已在过敏性疾病、癌症免疫治疗、HIV和COVID-19治疗中展示了积极效果[65-66]。应加强基础与临床的结合,为认知障碍性疾病的治疗提供更多靶点和新策略。最后,由于目前对于特定趋化因子和具体认知障碍性疾病的深入研究较少,因此本综述主要总结了趋化因子及其受体在认知障碍性疾病中的研究进展。未来的研究应更多地聚焦于特定的趋化因子及其受体,特别是探讨其在具体认知障碍性疾病中的作用机制。这不仅有助于深化对疾病机制的理解,为认知障碍性疾病的诊断提供新的思路,还可为相关疾病的治疗带来新的希望。

参考文献

[1]

Wang XLu DPeng D,et al. Studying allosteric regulation of chemokines and antagonists using a nanoscale hCCR3 receptor sensor. Int J Biol Macromol2023253(Pt 4):126892.

[2]

Bachelerie FBen-Baruch ABurkhardt AM,et al. International union of basic and clinical pharmacology. Update on the extended family of chemokine receptors and introducing a new nomenclature for atypical chemokine receptors[J]. Pharmacol Rev201466(1):1-79.

[3]

Allen SJCrown SEHandel TM. Chemokine:receptor structure,interactions,and antagonism[J]. Annu Rev Immunol200725:787-820.

[4]

DeVries MEKelvin AAXu LL,et al. Defining the origins and evolution of the chemokine/chemokine receptor system[J]. J Immunol2006176(1):401-415.

[5]

Villeda SALuo JMosher KI,et al. The ageing systemic milieu negatively regulates neurogenesis and cognitive function[J]. Nature2011477(7362):90-94.

[6]

Huang JKhademi MFugger L,et al. Inflammation-related plasma and CSF biomarkers for multiple sclerosis[J]. Proc Natl Acad Sci USA2020117(23):12952-12960.

[7]

Sirivichayakul SKanchanatawan BThika S,et al. Eotaxin,an endogenous cognitive deteriorating chemokine(ECDC),is a major contributor to cognitive decline in normal people and to executive,memory,and sustained attention deficits,formal thought disorders,and psychopathology in schizophrenia patients[J]. Neurotox Res201935(1):122-138.

[8]

Teixeira ALGama CSRocha NP,et al. Revisiting the role of eotaxin-1/CCL11 in psychiatric disorders[J]. Front Psychiatry20189:241.

[9]

Díez-Cirarda MYus-Fuertes MSanchez-Sanchez R,et al. Hippocampal subfield abnormalities and biomarkers of pathologic brain changes:from SARS-CoV-2 acute infection to post-COVID syndrome[J]. EBioMedicine202394:104711.

[10]

Fernández-Castañeda ALu PWGeraghty AC,et al. Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation[J]. Cell2022185(14):2452-2468.

[11]

Xia MQQin SXWu LJ,et al. Immunohistochemical study of the beta-chemokine receptors CCR3 and CCR5 and their ligands in normal and Alzheimer’s disease brains[J]. Am J Pathol1998153(1):31-37.

[12]

Zhu CYXu BSun XH,et al. Targeting CCR3 to reduce amyloid-β production,tau hyperphosphorylation,and synaptic loss in a mouse model of Alzheimer’s disease[J]. Mol Neurobiol201754(10):7964-7978.

[13]

Rege SVTeichert AMasumi J,et al. CCR3 plays a role in murine age-related cognitive changes and T-cell infiltration into the brain[J]. Commun Biol20236(1):292.

[14]

Janssen KRickert MClarner T,et al. Absence of CCL2 and CCL3 ameliorates central nervous system grey matter but not white matter demyelination in the presence of an intact blood-brain barrier[J]. Mol Neurobiol201653(3):1551-1564.

[15]

Conductier GBlondeau NGuyon A,et al. The role of monocyte chemoattractant protein MCP1/CCL2 in neuroinflammatory diseases[J]. J Neuroimmunol2010224(1/2):93-100.

[16]

Kooij GMizee MRvan Horssen J,et al. Adenosine triphosphate-binding cassette transporters mediate chemokine(C-C motif) ligand 2 secretion from reactive astrocytes:relevance to multiple sclerosis pathogenesis[J]. Brain2011134(2):555-570.

[17]

Wesselingh RGriffith SBroadley J,et al. Peripheral monocytes and soluble biomarkers in autoimmune encephalitis[J]. J Autoimmun2023135:103000.

[18]

Melamud MMErmakov EABoiko AS,et al. Multiplex analysis of serum cytokine profiles in systemic lupus erythematosus and multiple sclerosis[J]. Int J Mol Sci202223(22):13829.

[19]

Sola-Sevilla NMesa-Lombardo AAleixo M,et al. SIRT2 inhibition rescues neurodegenerative pathology but increases systemic inflammation in a transgenic mouse model of Alzheimer’s disease[J]. J Neuroimmune Pharmacol202318(3):529-550.

[20]

Zhou FTSun YYXie XH,et al. Blood and CSF chemokines in Alzheimer’s disease and mild cognitive impairment:a systematic review and meta-analysis[J]. Alzheimers Res Ther202315(1):107.

[21]

Zhang KWang HPXu M,et al. Role of MCP-1 and CCR2 in ethanol-induced neuroinflammation and neurodegeneration in the developing brain[J]. J Neuroinflammation201815(1):197.

[22]

Cao FYang MCheng YQ,et al. Correlation analysis of monocyte chemoattractant protein-1 and clinical characteristics and cognitive impairment in type 2 diabetes mellitus comorbid major depressive disorder[J]. Front Aging Neurosci202315:1081393.

[23]

Wells AJVaranoske ANCoker NA,et al. Effect of β-alanine supplementation on monocyte recruitment and cognition during a 24-hour simulated military operation[J]. J Strength Cond Res202034(11):3042-3054.

[24]

Alghibiwi HAnsari MANadeem A,et al. DAPTA,a C-C chemokine receptor 5 (CCR5),leads to the downregulation of Notch/NF-κB signaling and proinflammatory mediators in CD40+ cells in experimental autoimmune encephalomyelitis model in SJL/J mice[J]. Biomedicines202311(6):1511.

[25]

Alemán-Ruiz CWang WYDingledine R,et al. Pharmacological inhibition of the inflammatory receptor CCR2 relieves the early deleterious consequences of status epilepticus[J]. Sci Rep202313(1):5651.

[26]

Andonegui GZelinski ELSchubert CL,et al. Targeting inflammatory monocytes in sepsis-associated encephalopathy and long-term cognitive impairment[J]. JCI Insight20183(9):e99364.

[27]

Kimura AYoshikura NHayashi Y,et al. Cerebrospinal fluid C-C motif chemokine ligand 2 correlates with brain atrophy and cognitive impairment in Alzheimer’s disease[J]. J Alzheimers Dis201861(2):581-588.

[28]

王志红,李雪莲,王剑梅. 白细胞介素-18、趋化因子配体2在血管性认知损害患者中的表达意义及诊断效能分析[J]. 中国现代医学杂志202232(1):75-80.

[29]

Wang ZHLi XLWang JM. Analysis of significance and diagnostic efficacy of IL-18 and C-C motif ligand 2 expressions in patients with vascular cognitive impairment[J]. China J Mod Med202232(1):75-80.

[30]

Raghu HLepus CMWang Q,et al. CCL2/CCR2,but not CCL5/CCR5,mediates monocyte recruitment,inflammation and cartilage destruction in osteoarthritis[J]. Ann Rheum Dis201776(5):914-922.

[31]

Lin HYCathomas FLi L,et al. Chemokine receptor 5 signaling in PFC mediates stress susceptibility in female mice[J]. bioRxiv2023:2023.08.18.553789.

[32]

Shikuma CMWojna VDe Gruttola V,et al. Impact of antiretroviral therapy intensification with C-C motif chemokine receptor 5 antagonist maraviroc on HIV-associated neurocognitive impairment[J]. AIDS202337(13):1987-1995.

[33]

Li XZhang DFBi R,et al. Convergent transcriptomic and genomic evidence supporting a dysregulation of CXCL16 and CCL5 in Alzheimer’s disease[J]. Alzheimers Res Ther202315(1):17.

[34]

Festa BPSiddiqi FHJimenez-Sanchez M,et al. Microglial cytokines poison neuronal autophagy via CCR5,a druggable target[J]. Autophagy202420(4):949-951.

[35]

Galimberti DBonsi RFenoglio C,et al. Inflammatory molecules in Frontotemporal Dementia:cerebrospinal fluid signature of progranulin mutation carriers[J]. Brain Behav Immun201549:182-187.

[36]

Guedes JRLao TTCardoso AL,et al. Roles of microglial and monocyte chemokines and their receptors in regulating Alzheimer’s disease-associated amyloid-β and tau pathologies[J]. Front Neurol20189:549.

[37]

Rocha NPScalzo PLBarbosa IG,et al. Cognitive status correlates with CXCL10/IP-10 levels in Parkinson’s disease[J]. Parkinsons Dis20142014:903796.

[38]

Xia MQBacskai BJKnowles RB,et al. Expression of the chemokine receptor CXCR3 on neurons and the elevated expression of its ligand IP-10 in reactive astrocytes:in vitro ERK1/2 activation and role in Alzheimer’s disease[J]. J Neuroimmunol2000108(1/2):227-235.

[39]

Jorfi MPark JHall CK,et al. Infiltrating CD8+ T cells exacerbate Alzheimer’s disease pathology in a 3D human neuroimmune axis model[J]. Nat Neurosci202326(9):1489-1504.

[40]

Licht-Murava AMeadows SMPalaguachi F,et al. Astrocytic TDP-43 dysregulation impairs memory by modulating antiviral pathways and interferon-inducible chemokines[J]. Sci Adv20239(16):eade1282.

[41]

Krauthausen MKummer MPZimmermann J,et al. CXCR3 promotes plaque formation and behavioral deficits in an Alzheimer’s disease model[J]. J Clin Invest2015125(1):365-378.

[42]

de Jong EKde Haas AHBrouwer N,et al. Expression of CXCL4 in microglia in vitro and in vivo and its possible signaling through CXCR3[J]. J Neurochem2008105(5):1726-1736.

[43]

van Weering HRJBoddeke HWGMVinet J,et al. CXCL10/CXCR3 signaling in glia cells differentially affects NMDA-induced cell death in CA and DG neurons of the mouse hippocampus[J]. Hippocampus201121(2):220-232.

[44]

Jang EKim JHLee S,et al. Phenotypic polarization of activated astrocytes:the critical role of lipocalin-2 in the classical inflammatory activation of astrocytes[J]. J Immunol2013191(10):5204-5219.

[45]

Lee EChung WS. Glial control of synapse number in healthy and diseased brain[J]. Front Cell Neurosci201913:42.

[46]

Ball JBGreen-Fulgham SMWatkins LR. Mechanisms of microglia-mediated synapse turnover and synaptogenesis[J]. Prog Neurobiol2022218:102336.

[47]

Fernández de Cossío LGuzmán Avan der Veldt S,et al. Prenatal infection leads to ASD-like behavior and altered synaptic pruning in the mouse offspring[J]. Brain Behav Immun201763:88-98.

[48]

Wang LLing HYHe H,et al. Dysfunctional synaptic pruning by microglia correlates with cognitive impairment in sleep-deprived mice:Involvement of CX3CR1 signaling[J]. Neurobiol Stress202325:100553.

[49]

Ge YYWang LWang CC,et al. CX3CL1 inhibits NLRP3 inflammasome-induced microglial pyroptosis and improves neuronal function in mice with experimentally-induced ischemic stroke[J]. Life Sci2022300:120564.

[50]

Subbarayan MSJoly-Amado ABickford PC,et al. CX3CL1/CX3CR1 signaling targets for the treatment of neurodegenerative diseases[J]. Pharmacol Ther2022231:107989.

[51]

吴昊天,彭友谊,龚彩平, 趋化因子CCL3在感染性疾病中的诊断价值[J]. 中山大学学报(医学科学版)202546(3):506-511.

[52]

Wu HTPeng YYGong CP,et al. Diagnostic value of chemokine CCL3 in infectious diseases[J]. J Sun Yat Sen Univ Med Sci202546(3):506-511.

[53]

Zhang QXHe LChen M,et al. PSD-93 mediates the crosstalk between neuron and microglia and facilitates acute ischemic stroke injury by binding to CX3CL1[J]. J Neurochem2021157(6):2145-2157.

[54]

刘 畅,张 申,周菲惠, CX3CR1通过调节Ca2+内流介导神经元凋亡影响缺血性卒中小鼠预后[J]. 基础医学与临床20206(1):1-8.

[55]

Liu CZhang SZhou FH,et al. CX3CR1 mediates neuronal apoptosis by regulating Ca2+ influx to affect the prognosis of ischemic stroke mice[J]. Basic Clin Med20206(1):1-8.

[56]

Huang HXia AQSun L,et al. Pathogenic functions of tumor necrosis factor receptor-Associated factor 6 signaling Following traumatic brain injury[J]. Front Mol Neurosci202114:629910.

[57]

Zhao KZhou XKChen MY,et al. Neuroprotective effects of CXCR2 antagonist SB332235 on traumatic brain injury through suppressing NLRP3 inflammasome[J]. Neurochem Res202449(1):184-198.

[58]

Serdar MKempe KHerrmann R,et al. Involvement of CXCL1/CXCR2 during microglia activation following inflammation-sensitized hypoxic-ischemic brain injury in neonatal rats[J]. Front Neurol202011:540878.

[59]

Boro MBalaji KN. CXCL1 and CXCL2 regulate NLRP3 inflammasome activation via G-protein-coupled receptor CXCR2[J]. J Immunol2017199(5):1660-1671.

[60]

Wang HYHuang QBZhang ZJ,et al. Transient post-operative overexpression of CXCR2 on monocytes of traumatic brain injury patients drives monocyte chemotaxis toward cerebrospinal fluid and enhances monocyte-mediated immunogenic cell death of neurons in vitro [J]. J Neuroinflammation202219(1):171.

[61]

Xia AQHuang HYou WJ,et al. The neuroprotection of hyperbaric oxygen therapy against traumatic brain injury via NF-κB/MAPKs-CXCL1 signaling pathways[J]. Exp Brain Res2022240(1):207-220.

[62]

Abdelaziz RRAbdelrahman RSAbdelmageed ME. SB332235,a CXCR2 antagonist,ameliorates thioacetamide-induced hepatic encephalopathy through modulation of the PI3K/AKT pathways in rats[J]. Neurotoxicology202292:110-121.

[63]

Albekairi NANadeem AAnsari MA,et al. CXCR2 antagonist SB332235 mitigates deficits in social behavior and dysregulation of Th1/Th22 and T regulatory cell-related transcription factor signaling in male BTBR T+ Itpr3tf/J mouse model of autism[J]. Pharmacol Biochem Behav2022217:173408.

[64]

Mai CLTan ZXu YN,et al. CXCL12-mediated monocyte transmigration into brain perivascular space leads to neuroinflammation and memory deficit in neuropathic pain[J]. Theranostics202111(3):1059-1078.

[65]

Farooqui MOrtega-Gutierrez SHernandez K,et al. Hyperacute immune responses associate with immediate neuropathology and motor dysfunction in large vessel occlusions[J]. Ann Clin Transl Neurol202310(2):276-291.

[66]

Piehl Nvan Olst LRamakrishnan A,et al. Cerebrospinal fluid immune dysregulation during healthy brain aging and cognitive impairment[J]. Cell2022185(26):5028-5039.

[67]

Sheu MLPan LYYang CN,et al. Neuronal death caused by HMGB1-evoked via inflammasomes from thrombin-activated microglia cells[J]. Int J Mol Sci202324(16):12664.

[68]

Mollica Poeta VMassara MCapucetti A,et al. Chemokines and chemokine receptors:new targets for cancer immunotherapy[J]. Front Immunol201910:379.

[69]

Do HTTLee CHCho J. Chemokines and their receptors:multifaceted roles in cancer progression and potential value as cancer prognostic markers[J]. Cancers202012(2):287.

基金资助

国家自然科学基金重点资助项目(21AH0103)

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