摘 要：阿尔茨海默病（Alzheimer disease，AD）是一种以痴呆为主要症状的慢性进行性神经退行性疾病，主要神经病理学特征包括老年斑、神经原纤维缠结、神经炎症和神经元丢失。AD中的β-淀粉样蛋白沉积和错误折叠的Tau蛋白诱导小胶质细胞的激活，引起细胞因子、趋化因子的分泌，共同形成神经炎症反应影响AD的发展。本文总结了小胶质细胞激活和趋化因子释放在AD神经炎症中发挥的作用，为AD的治疗提供新的思路。
关键词：趋化因子; 小胶质细胞; 神经炎症; 阿尔茨海默病;
Progress in research on the role of chemokines and microglia in the neuroinflammation of Alzheimer’s disease
WANG Jia ZHANG Li WEI Heru ZHAI Yueyi LIU Shufeng ZHANG Lianfeng
Hebei Key Lab of Laboratory Animal science, Hebei Medical University Key Laboratory of Human Disease Comparative Medicine, National Health and Family Planning Commission of P.R.C, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Comparative Medicine Center, Peking Union Medical College
Abstract：
Alzheimer’s disease (AD) is a chronic progressive neurodegenerative disease characterized by dementia as the main symptom. The main neuropathologic features include senile plaques, neurofibrillary tangles, neuroinflammation, and neuron loss. Deposition of amyloid β-protein and misfolded tau protein in patients with AD induces the activation of microglia; this leads to the secretion of cytokines and chemokines, which jointly induce a neuroinflammatory response and affect the progression of AD. This review briefly summarizes the role of microglial activation and chemokine release in the neuroinflammation of AD and provides new insight into the treatment of AD.
Keyword：
chemokines; microglia; neuroinflammation; Alzheimer's disease;
阿尔茨海默病（Alzheimer disease，AD）是一种常见的慢性进行性神经退行性疾病，主要临床表现为进行性认知功能障碍、精神和行为异常，逐渐发展为无法进行日常生活的严重痴呆。AD主要病理学改变有大脑皮质区和海马区的细胞外β-淀粉样蛋白（amyloid β-protein，Aβ）沉积形成的老年斑（senile plaques，SP）、神经细胞内过度磷酸化的Tau蛋白错误折叠后聚集形成的神经原纤维缠结（neurofibrillary tangles，NFTs）、神经炎症和神经元丢失[1]。目前，AD的发病原因与发病机制尚不明确，经典的病因假说有Aβ级联假说和Tau蛋白假说等。越来越多证据显示神经炎症在AD发病中具重要作用，神经炎症是中枢神经系统（central nervous system，CNS）针对各种有害刺激（如损伤或感染）发生的免疫反应，由CNS的神经胶质细胞、内皮细胞和外周的免疫细胞介导并产生细胞因子、趋化因子、活性氧等各种炎性介质共同引起[2]。AD病理研究发现SP附近存在反应性小胶质细胞，同时检测到AD病人脑实质中炎性细胞因子和趋化因子（chemokine，CK）的水平升高，揭示AD中存在神经炎症，并参与AD的发病机制[1,3]。AD中的神经炎症主要以Aβ沉积和错误折叠的Tau蛋白对小胶质细胞的持续激活，导致细胞因子和趋化因子等炎性介质的不断释放产生的慢性炎症反应，而释放的趋化因子诱导小胶质细胞向神经炎症区域迁移，发挥促炎或抗炎的作用，进而影响AD的发展[4]。因此，本文将重点论述小胶质细胞激活和趋化因子释放在AD神经炎症中发挥的作用。
1 小胶质细胞的激活
小胶质细胞是神经胶质细胞的一种，大约占大脑中神经胶质细胞的10%左右。研究表明小胶质细胞起源于卵黄囊的原始巨噬细胞，相当于脑和脊髓中的巨噬细胞[5]。静息的小胶质细胞以休眠模式监视着周围组织的免疫状态，当出现炎症刺激时，小胶质细胞迅速被激活，通过改变形态迁移至病变部位，清除坏死物质，支持和保护神经系统。激活后的小胶质细胞可以极化为促炎或抗炎表型，分别称为经典激活小胶质细胞（M1型）和替代激活小胶质细胞（M2型）[6]。M1型为促炎状态，释放大量促炎因子（如IL-1β、TNF-α、IFN-γ、CCL2）以及一氧化氮合酶iNOS，活性氧ROS等炎性成分，不断加剧炎症反应，引起神经元变性及脑组织损伤。M2型为抗炎状态，能够释放抗炎因子（如IL-4、IL-10、IL-13、YM-1）以及神经营养因子促进炎症消退，吞噬细胞碎片，促进组织修复并重建体内稳态[6,7,8]。
AD产生的Aβ沉积、错误折叠的Tau蛋白及损伤的神经元会吸引小胶质细胞的聚集并引起其激活，同时引起细胞因子和趋化因子的释放，这些因素与Aβ持续相互作用形成AD中的神经炎症[9,10]。AD病理研究中发现Aβ可以诱导小胶质细胞的聚集并浸润在淀粉样斑块周围，Aβ可以作为危险相关分子模式激活小胶质细胞表面模式识别受体如Toll样受体（Toll-like receptors，TLR），髓样细胞触发受体2（triggering receptor expressed on myeloid cells，TREM2），清道夫受体（scavenger receptor，SR-AI/II），补体受体，受体晚期糖基化终产物（receptor advanced glycosylation end product，RAGE）等，引起小胶质细胞的活化、分泌、吞噬等作用[11,12]。Aβ还可以直接以浓度依赖的方式与淀粉样前体蛋白（amyloid precursor protein，APP）相互作用，共同诱导小胶质细胞的激活并分泌炎性因子TNF-α[13]。Nussbaum等[14]发现Aβ还能诱导Tau蛋白异常聚集，并在细胞内形成NFTs而引发慢性神经炎症。相关研究报道在AD患者海马体的NFTs和带有缠结的神经元附近，以及Tau蛋白转基因动物模型（TAUSHR72转基因大鼠和TauR406W转基因小鼠）中，常出现小胶质细胞的激活，可能的原因是当Tau蛋白发生错误折叠后，不断聚集并在神经元中形成NFTs，破坏神经元的功能并导致细胞最后死亡，引发的炎症激活小胶质细胞。这些均表明炎症反应与NFTs之间存在密切关系[10,15,16]。同时激活的小胶质细胞释放的TNF-α会在体外诱导Tau蛋白的聚集[17]。因此，Aβ沉积和错误折叠的Tau蛋白可以通过多种途径激活小胶质细胞炎症反应路径，并进一步影响AD的发生、发展。
静息的小胶质细胞在AD产生的病理中可以诱导激活为M1型和M2型。目前的研究认为在AD的早期，Aβ沉积将静止的小胶质细胞激活为M2型，M2型极化的小胶质细胞表现表现出神经保护和抗炎作用，分泌抗炎因子，吞噬、降解、去除Aβ和Tau，抑制炎症反应。随着AD病理发展，Aβ和Aβ诱导的促炎因子持续相互作用使小胶质细胞过度活化转变为M1型，M1型的小胶质细胞表现出神经毒性和促炎作用，释放大量促炎因子，运动能力下降，吞噬、降解能力减弱，加剧炎症反应[18,19]。图1为小胶质细胞在AD中的激活。从图中发现，AD中激活的M1型小胶质细胞可以引起促炎性趋化因子（CCL2、CCL3、CCL4、CCL5、CXCL1、CXCL8、CXCL9、CXCL10）的分泌，M2型小胶质细胞引起抗炎性趋化因子（CCL22、CXCL8、CXCL12、CX3CL1）的分泌[20,21,22,23]。由此可见，小胶质细胞的极化过程中会引起大量趋化因子的分泌，这些趋化因子与小胶质细胞相互作用，共同影响AD的进程。因此，下文将对趋化因子分类总结并分别展开论述。
图1 小胶质细胞在AD中的激活过程
2 趋化因子的分泌
趋化因子是一类促使细胞分化、迁移和运输功能的多肽，能够激活趋化因子受体，在炎症过程中诱导趋化、组织外渗以及调节白细胞的功能[24]。趋化因子及其受体在大脑中以低水平表达，受到炎症刺激才会发生调节作用，其表达主要来源于小胶质细胞及其他神经细胞 [25]。趋化因子根据分子中N-末端半胱氨酸的不同位置分为四个亚家族，包括CXC、CC、C和CX3C。其中CXC趋化因子亚族17个成员，C趋化因子亚族2个成员，CX3C趋化因子亚族1个成员。而CC趋化因子则是趋化因子家族中最大的亚类，包括28个成员，分别为CCL1~CCL28。CXC趋化因子家族成员中CXCL1、CXCL9、CXCL10在AD中上调，参与促炎反应[22,23]。CX3C家族的唯一成员CX3CL1发现具有抑制Tau蛋白病理改变，增加神经信号传导和神经保护作用[26]。更多的研究发现大量的CC趋化因子在AD中上调，少量因子存在下调或者不变[27]，且其受体CCR3，CCR5阳性反应的小胶质细胞与Aβ沉积密切相关[28]。提示了CC趋化因子在AD中可能的重要作用和未来研究方向。因此，本文重点论述CC趋化因子在AD神经炎症和小胶质细胞的激活中的重要作用。28个CC趋化因子的受体、功能和在AD中的表达变化总结见表1。根据28个CC趋化因子目前已发现的炎症调节作用将其分为三类：促炎性、抗炎性和双重功能的趋化因子。分述见表1。
表1 CC趋化因子的功能及其受体
2.1促炎性趋化因子
促炎因子对炎症的发展有促进作用。大多数表现出促炎作用的趋化因子在AD及其产生的神经炎症中是上调的，如表1中CCL2、CCL3、CCL4、CCL5、CCL6、CCL9、CCL11、CCL12、CCL15，这些趋化因子不单表现参与炎症反应，也在AD的病理机制中发挥特有的作用，并且和其本身的氨基酸序列同源性密切相关。
CCL2，又称为单核细胞趋化蛋白（monocyte chemoattractant protein，MCP-1），由淀粉样斑块相关的小胶质细胞产生，Kiyota等[75]的研究发现CCL2过表达的Tg2576（APPswe）/CCL2转基因小鼠表现出小胶质细胞的聚集和促进Aβ沉积和淀粉样斑块形成，并加速了认知障碍。CCL2过表达使rTg4510（tauP301L）转基因小鼠模型的Tau蛋白病理恶化，表现以NFTs和磷酸化Tau阳性包涵体的大量增加，并伴有胶质细胞增生和明显的炎症反应[76]。另一研究表明CCL2在遗忘性轻度认知障碍（amnestic mild cognitive impairment，aMCI）、AD及同样具有痴呆、脑萎缩特征的额颞叶型失智症（Frontotemporal dementia，FTLD）患者的脑脊液（cerebrospinal fluid，CSF）中均明显升高[77,78]。CCL12（MCP-5）是与CCL2（MCP-1）同源的单核细胞趋化因子，具有66％的氨基酸同一性。CCL2与CCL12都是Tau病理相关神经炎症的压力应激反应基因[46]。CCL2和CCL12还可以同时与CCR2受体结合，CCR2在小胶质细胞上具有迅速促进嘌呤能受体（purinergic receptor，P2RX4）转运到细胞表面的能力，进而促进小胶质细胞的胞吐作用[79]。脊髓中星形胶质细胞表达的CCL7（MCP-3）和CCL2（MCP-1）具有大于60%的氨基酸同一性，也可以通过CCR2激活小胶质细胞，产生更多炎性介质引起神经性疼痛[37,80]。根据以上证据说明具有同源性基因的趋化因子可以与同一种受体结合，对炎症刺激发挥同样的促炎功能。
然而这一现象并不是完全一致的，有研究报道在212名FTLD患者与203名年龄匹配的对照人群观察CCL2（MCP-1）A-2518G的单核苷酸多态性（single nucleotide polymorphism，SNP），FTLD患者脑脊液中MCP-1水平显著高于对照组，MCP-1 A-2518G SNP可能通过影响MCP-1的产生而成为FTLD的保护因子[81]。CCL2和CCL8（MCP-2）同样具有相似序列的趋化因子，其氨基酸序列同源性为62%，均会在神经退行性疾病中升高[80]。在CCL8中发现SNP与CCL2都位于同一连锁区，其中rs1163763会导致氨基酸的取代，对蛋白质功能产生潜在的影响，对219名AD患者和209名FTLD患者进行了rs1133763关联测试，并与231名年龄相匹配的对照组进行比较，发现CCL8 rs1133763的分布在患者和对照组之间没有显着差异。这种SNP相关的连锁不平衡基因变异对神经退行性疾病并无明显作用[40]。因此，即使是具有同源性基因的趋化因子在神经疾病中也会发挥各自不同的功能。
CCL3/巨噬细胞炎性蛋白-1α（Macrophage inflammatory protein，MIP-1α）和CCL4/巨噬细胞炎性蛋白-1β（Macrophage inflammatory protein，MIP-1β）是巨噬细胞炎性蛋白（MIP-1）的两种形式，二者相互作用，共用同一受体CCR5，其功能与炎症反应有关[82]。5XFAD转基因小鼠中淀粉样斑块相关的小胶质细胞表现出免疫反应过度和炎症的高反应性，同时发现促炎因子CCL3、CCL4、CCL6的表达[9]。Passos等[83]的研究也发现在小鼠侧脑室注射Aβ1–40后，CCL3及其受体CCR5的表达水平升高，小胶质细胞的数量也显著增加。遗传方面CCL3/MIP-1α的基因多态性影响中国人对AD的敏感性，其中MIP-1α-906（TA）6/（TA）6基因可能是AD的遗传危险因素[84]。研究发现AD患者的外周血单核细胞控制着CCL4的产生[85]，AD的APPswe/PS1dE9转基因小鼠大脑的CCL4水平升高与大脑Aβ沉积呈年龄依赖性相关，并增加淀粉样斑块周围星形胶质细胞的活化，放大了炎症反应[86]。
2.2抗炎性趋化因子
抗炎因子被认为可以减轻炎症反应。目前明确具有抗炎作用的趋化因子CCL17、CCL18、CCL22在有关AD疾病中的研究较少，但在影响大脑认知、神经炎症、小胶质细胞的激活等神经系统相关研究中发现了很多可能会影响AD疾病发展的抗炎作用。
CCL17，即胸腺和激活调节趋化因子（thymus and activation-regulated chemokine，TARC），是M2型巨噬细胞的标志物，IL-4可以诱导其在巨噬细胞中形成和上调，激活的M2型巨噬细胞参与吞噬细胞碎片以及抑制炎症反应[55]。维生素D3可选择性地增强小胶质细胞HMO6中细胞因子IL-10和CCL17的表达，使小胶质细胞具有抗炎活性，保护神经进行免疫修复[56]。在应对LPS诱导的急性炎症刺激时，与记忆认知有关的海马CA1区小胶质细胞的CCL17上调，CCL17可以维持小胶质细胞的静息状态，CCL17基因敲除小鼠（CCL17-/-）的小胶质细胞体积减少，并呈现出分枝减少、极性增强的反应形态[87]。一项针对高罹患AD疾病风险的墨西哥裔美国人关于遗忘性轻度认知障碍的生物标记物检测发现在aMCI病例中血液生物标记物以炎性因子为主，排列前三的标记物分别为TNFα，IL-10和TARC，这些发现提示了炎性因子和aMCI发展至AD的代谢过程可能存在相互作用，还需要对上述炎性因子进一步研究[88]。
CCR4是CCL17和CCL22/巨噬细胞来源的趋化因子（macrophage-derived chemokine，MDC）的共同受体，CCR4的基因敲除小鼠（CCR4-/-）表现出运动和探索行为受损，此时的CCR4与其配体CCL22可能参与了神经元和神经胶质细胞的功能调节[89]。CCL22在实验性自身免疫性脑脊髓炎（experimental autoimmune encephalomyelitis，EAE）小鼠的大脑中由小胶质细胞产生，通过诱导TH2细胞的归巢来调节Th1细胞介导的神经炎症[90]。CCL22同样具有抗炎活性，在神经系统疾病的脱髓鞘、神经元损伤中，都检测到了M2型小胶质细胞标志物IL-10、CCL18、CCL22，激活的M2型小胶质细胞有助于免疫抑制，促进神经修复和髓鞘的再生[91]。Movsesyan等的研究团队[92,93]设计以CCL22作为分子佐剂的AD疫苗PMDC-3Aβ 1-11-PADRE，通过诱发细胞免疫及体液免疫，产生抗炎作用，减轻炎症反应，协同疫苗产生的抗Aβ抗体共同促进APPSwe/PS1M146V/tauP301L转基因小鼠大脑中Aβ沉积物的清除，抑制Aβ病理学的积累。
CCL18也称为替代巨噬细胞活化相关趋化因子-1（alternative macrophage activation associated chemokine，AMAC-1）和巨噬细胞炎性蛋白-4（MIP-4），它与CCL3关系最密切，共享64％的序列同一性，却没有激活与CCL3相同的受体，因为CCL18具有独特的四级结构，可以和CCR8、PITPNM3、GPR30三种受体结合，表现出抗炎性趋化因子的作用。CCL18作为人和灵长类动物独有的趋化因子，从死亡后人脑组织分离出来的小胶质细胞在IL-4刺激下培养，发现了CCL18上调[94]。在没有IL-4的刺激，CCL18也可以诱导单核细胞成为M2型巨噬细胞，上调抗炎因子IL-10，并增强巨噬细胞的吞噬能力，清除细胞碎片[57]。
2.3 双重功能趋化因子
有学者在炎症相关研究中发现个别趋化因子具有促炎和抗炎的双重作用，即在不同的炎症环境中可以表现出促炎状态也可以表现出抗炎状态，如CCL1、CCL2、CCL7、CCL13、CCL14、CCL23、CCL24、CCL26。CCL1、CCL2、CCL7在神经炎症中表现出以促炎作用为主，而另外一些具有双重功能的趋化因子在AD和神经炎症中的作用并不十分明确。
CCL23是具有促炎和抗炎双重功能的趋化因子，在单核细胞中既能被IL-1β和IFN-γ诱导表达，也能由IL-4和IL-13诱导表达，在树突状细胞由IL-10诱导使其表达[65]。临床研究表明AD患者血液中的CCL23高于健康对照者，从轻度认知障碍（mild cognitive impaired，MCI）发展到AD患者的血液及脑脊液检测数据中发现CCL23呈高进展性，并且在AD遗传易感因素ApoE ɛ4等位基因携带者血液中检测到高水平的CCL23，可能与血浆中的炎症反应有关，预测CCL23可能是轻度认知障碍发展到AD的血液生物炎性标志物[66]。CCL23的受体CCR1，只在与Aβ42阳性的神经炎斑和营养不良性神经元中表达，并且随临床疾病的严重程度而增加，因此成为AD特有的神经炎性标志物[95]。
CCL26又称嗜酸性粒细胞趋化因子（Eotaxin-3），已证明IL-4和IL-13可通过JAK1-STAT6途径上调CCL26的表达，表现出抗炎作用，但同时TNF-α对IL-4增强的CCL26产生协同作用[96]。在EAE大鼠的神经炎症反应中，CCL26结合CCR3发挥促炎作用，加重脑组织损伤[70]。在轻度认知障碍发展至AD的临床随访研究中发现前驱性AD患者脑脊液中的CCL26显著高于健康对照者[31]。
3 小结与展望
无论是衰老、遗传或者环境因素造成的痴呆，都会在AD病理形成的过程中产生神经炎症。小胶质细胞是大脑中免疫监视器，也是神经炎症反应的核心。小胶质细胞作为AD清除Aβ的主要途径，可以抑制淀粉样蛋白的沉积延缓AD的发展；但炎性持续激活的小胶质细胞会分泌更多的促炎因子，引起神经元的损伤，加速AD的进展。小胶质细胞是AD的疾病发展的一把双刃剑，如何抑制M1型小胶质细胞的炎性激活，减轻炎症反应，增加M2型小胶质细胞的神经保护作用，维持稳态的正性平衡成为治疗AD疾病的方向。
趋化因子在AD的神经炎症反应中具有双向调节的作用，一方面具有促炎作用的趋化因子可以持续激活M1型小胶质细胞分泌更多炎性因子及毒性物质，使小胶质细胞失控，加重炎症反应，形成恶性循环；另一方具有抗炎作用的趋化因子可以维持M2型小胶质细胞的稳态，增加Aβ内化及降解，减轻炎症的活跃程度。这是一个高度动态的过程，神经炎症中的促炎和抗炎因子对于正常细胞组织代谢的动态平衡至关重要，如何维持稳态平衡决定了炎症反应的发展。AD疾病中的神经炎症活跃程度由趋化因子、细胞因子等炎性介质所反应，抗炎因子和促炎因子的平衡影响着AD的预后。很多研究将促炎性趋化因子CCL2、CCL3作为MCI发展到AD早期的炎性因子标志物，也有将具有抗炎作用的CCL22作为分子佐剂的AD疫苗，但更多关于趋化因子的研究只是检测其在AD中的水平变化，并没有深入探索这些趋化因子对于小胶质细胞或者Aβ诱导神经炎症的作用机制研究。因此需要明确抗炎性趋化因子控制小胶质细胞表型转换的机制，进而可以通过增加抗炎性趋化因子的正向作用和减少促炎性趋化因子的负向作用来改善AD的神经炎症程度，为AD的治疗提供新的思路。
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