徐曼曼 晁斌 崔翰明
[摘要] 小胶质细胞广泛分布于中枢神经系统,是其固有的免疫细胞,其介导的神经炎症是引发脑白质损伤的重要因素。越来越多证据表明,不同脑白质损伤疾病中小胶质细胞激活的路径各有差异,这是其在中枢神经系统发挥复杂作用的基础。脑白质损伤的典型表现就是脱髓鞘,脱髓鞘存在于包括多发性硬化症、阿尔茨海默病、血管性认知障碍和痴呆等在内的多种疾病的共同病理阶段中。本文探讨了多种疾病类型及所在不同大脑区域下,小胶质细胞通过不同激活途径发挥生物学作用的医学机制。此外,小胶质细胞在脑白质损伤中可发挥促炎和免疫调节的双相作用,对这些小胶质细胞亚型的进一步研究可能会衍生出新的治疗方法,促进脑白质损伤的修复。
[关键词] 小胶质细胞;神经炎症;脑白质损伤;脱髓鞘
[中图分类号] R742 [文献标识码] A [文章编号] 1673-7210(2020)10(b)-0037-04
[Abstract] Microglia is widely distributed in the central nervous system and is the inherent immune cells. The nerve inflammation mediated by microglia is an important factor that cause white matter damage. More and more evidences show that the activation pathways of microglia in different white matter damage diseases are different, which is the basis of their complex role in the central nervous system. The typical manifestation of white matter damage is demyelination, which is a common pathological stage in multiple diseases including multiple sclerosis, Alzheimer′s disease, vascular cognitive impairment and dementia. In this article, the medical mechanism for microglia playing biological role through different activation pathways under various disease types and different brain regions is discussed. In addition, microglia can play a biphasic role in brain white matter damage, such as proinflammatory and immunomodulatory effects, therefore further research on these microglial subtypes may lead to new treatments that promote the repair of white matter damage.
[Key words] Microglia; Nerve inflammation; White matter damage; Demyelination
小胶质细胞是中枢神经系统固有的免疫细胞和免疫监视细胞,占中枢神经系统细胞的10%~15%,相当于定居在脑和脊髓中的巨噬细胞。这些细胞通过检查周围微环境损伤[损伤相关分子模式(DAMPs)]或感染指标[病原体相关分子模式(PAMPs)]发挥作用,促进脑稳态[1]。当发现异常时,小胶质细胞的吞噬作用迅速被激活,清除细胞碎片和死亡的神经元。但是在此过程中,小胶质细胞释放的促炎分子也对中枢神经系统其他成分(包括神经元和少突胶质细胞)产生细胞毒性作用,进而引发疾病[2]。然而相关研究报道了小胶质细胞的保护作用,与传统有害作用不同,其可促进脑白质中髓磷脂的再生[3]。因此,人们认识到脑白质损伤时神经元疾病的病理状态不同,小胶质细胞所发挥的功能也不同。
脑白质主要包括有髓神经的轴突,其连接大脑各个区域的神经元,在人类大脑的近一半区域,脑白质的髓鞘形成是认知、记忆、运动和复杂技能发展所必需的[4]。因此,脑白质的损害或异常会导致多种神经元疾病,如多发性硬化症(MS)[5]、阿尔茨海默病(AD)[6]、创伤性脑损伤(TBI)[7]、血管性认知障碍和痴呆(VCID)[8]等。另外,脑白质的结构变化或髓磷脂基因的异常也是精神疾病的危險因素[9],如抑郁症、精神分裂症和强迫症。因此,脑白质中的髓鞘形成对于脑功能的正常发育和维持至关重要。本文探讨了脑白质损伤期间小胶质细胞的变化,重点了解这些变化如何影响疾病的进展及针对于此的潜在疗法,以便更好指导临床。
1 小胶质细胞在脑白质损伤中的激活途径
1.1 经典激活途径
当小胶质细胞以经典途径在各种与脑白质有关的疾病中被“激活”时,可高表达促炎细胞因子,主要有组织相容性复合物Ⅱ(MHCⅡ)及其共刺激因子CD40和CD86(也称为B7-2),也是MS和AD中小胶质细胞激活的经典标志物[10]。在自身免疫性脑脊髓炎(EAE)的动物实验中也观察到了这一点,随着小胶质细胞的增殖,CD45、MHCⅡ、CD40和CD86的表达也相应增加[11]。同样在缺血性痴呆模型中也观察到类似现象,结果显示脑白质中的小胶质细胞和巨噬细胞在灌注不足3 d时MHC-Ⅰ/Ⅱ或基质金属蛋白酶2(MMP-2)的表达升高,提示脑灌注不足后小胶质细胞可被提前激活[12]。而肌肽(β-丙氨酰-L-组氨酸,一种在中枢神经系统中高度表达的天然二肽)的治疗可导致小鼠的小胶质细胞失活,改善患者的认知障碍和脑白质病变[13]。以上研究观察到小胶质细胞的增殖及其激活主要发生在疾病早期,特别是在脱髓鞘的活性部位,而在疾病恢复后期未观察到这些变化[14]。
1.2 其他激活途徑
小胶质细胞的极化不是表型的单一变化,而是涉及空间和转录上不同亚群的动态反应,可以根据疾病病理状态和脑白质区域的不同而发生改变。Locatelli等[15]利用EAE小鼠进行实时体内成像,观察到小胶质细胞和单核巨噬细胞的时空演化。他们的分子表达模式从诱导型一氧化氮合酶(NOS)等促炎标志物转变为包括精氨酸酶在内的免疫调节标志物,提示小胶质细胞亚型可以根据EAE病变的病理状态进行自我调节。此外,Simpson等[16]研究了老年患者脑白质病变的小胶质细胞,发现脑室周围病变中表达MHCⅡ、CD40和B7-2的小胶质细胞明显多于对照组或深部皮层下病变,但脑室周围病变中存在的小胶质细胞形态呈分枝状和活化状,而皮层下病变中存在较多的变形虫和吞噬表型,反映小胶质细胞亚群激活途径依据病变部位的不同发生改变[17]。
总而言之,根据疾病类型及所在大脑区域,存在多种激活的小胶质细胞亚群,他们有助于判断与脑白质有关的疾病处于何种阶段。
2 小胶质细胞在脑白质损伤中的双相作用
2.1 促炎作用
经典激活途径中,活化的小胶质细胞会分泌参与炎症级联反应的促炎因子,促进神经系统疾病的脱髓鞘。脂多糖(LPS)激活的小胶质细胞,极化至促炎状态,分泌肿瘤坏死因子α(TNF-α)和白细胞介素1β(IL-1β),均对少突胶质细胞具有细胞毒性[18]。在大鼠原代少突胶质细胞培养物中,TNF-α和双环己酮草酰双腙(cuprizone)的共同处理可导致其细胞生存能力显著下降[19]。当给予cuprizone的小鼠中通过米诺环素对小胶质细胞的激活进行阻断时,脱髓鞘被阻止,反向证明小胶质细胞衍生因子对少突胶质细胞的毒性作用。此外,在大鼠细胞中观察到小胶质细胞产生的一氧化氮(NO)与少突胶质细胞死亡之间存在正相关,提示NO诱导的损伤是少突胶质细胞的毒性机制[20]。以上均提示小胶质细胞释放相关促炎介质可加重脑白质损伤。
2.2 免疫保护作用
另一方面,小胶质细胞在髓鞘再生阶段具有保护作用。MS模型中髓磷脂受损后,在髓鞘再生期间对胼胝体中的小胶质细胞进行了全基因组基因表达分析,发现其表达了一系列细胞因子和趋化因子,比如趋化因子(CXCL10)、转化生长因子b1(Tgfb1)和血小板衍生生长因子(Pdgfa、Pdgfb),这些因子可使少突胶质前体细胞(OPC)聚集到病变部位并分化,促进髓鞘再生[21]。还有研究发现缺血性损伤后小胶质细胞分泌转化生长因子α(TGF-α),体外实验证明对OPC和少突胶质细胞有保护作用,可能在体内有助于脑白质的修复[22]。然而,先前发现小胶质细胞分泌的TNF-α和IL-1β与其他促炎因子(例如CXCL13和内皮素2)一起在髓鞘再生中可发挥有益的作用[23],产生这种矛盾现象的原因是由于他们不同受体亚型的时间依赖性表达变化,或者在疾病后期次级髓鞘分泌因子导致,提示小胶质细胞在调节脑稳态中的复杂作用。
3 治疗方法
目前,尚未有批准的改善髓鞘再生的疗法,特别是没有针对小胶质细胞的疗法[24]。但是,已经有报道相关药物可降低小胶质细胞的神经炎症活性[25],达到缓解疾病的目的。在一项缺血性中风模型诱导的小鼠中,与对照组比较,体温过低降低了小胶质细胞的炎症表型并增加其免疫调节类型,促进了脑白质的自身修复[26]。Li等[27]通过运用VK-28{5-[4-(2-羟乙基)哌嗪-1-基甲基]-喹啉-8-ol,一种脑可渗透性铁螯合剂}治疗小鼠脑出血模型,通过对小胶质细胞极化,可使之变成免疫调节亚型并减少脑白质损伤。同样运用富马酸二甲酯(一种已知可抑制小胶质细胞炎症的药物)对100对患有严重脑灌注不足的小鼠治疗后,发现炎症性小胶质细胞和巨噬细胞数量均适度减少,而且脑白质的功能损害也得到了相应改善[28]。总体而言,这些研究提示通过直接靶向作用或者转化小胶质细胞亚型的方法可能是一种针对脑白质疾病新颖有效的疗法。因此通过调节小胶质细胞表型促进脑白质修复意义重大,如果有相关的潜在疗法,临床将大受裨益。
4 结语
在中枢神经系统疾病急性阶段,有害的小胶质细胞会促进炎症性微环境,涉及抗原呈递和促炎分子地分泌,从而触发脱髓鞘和神经元损伤。然而,在随后的恢复期,小胶质细胞的过度激活被减弱,其吞噬活性有助于清除髓磷脂碎片和死细胞。免疫调节小胶质细胞还分泌促进OPC迁移及其发育成少突胶质细胞的因子,从而促进髓鞘再生。尽管已经积累了多重有害与有益作用的证据,但这些相反现象所涉及的机制仍有待充分理解,针对于此的潜在疗法仍有待进一步挖掘。
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(收稿日期:2020-01-09)