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   大连医科大学学报  2020, Vol. 42 Issue (3): 258-261      DOI: 10.11724/jdmu.2020.03.15
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小胶质细胞/巨噬细胞极化对糖尿病合并缺血性脑损伤影响的研究进展
安露露, 韩江全, 官劲帆, 田明巧    
遵义医科大学第五附属(珠海)医院 神经内科, 广东 珠海 519100
摘要:糖尿病是脑卒中的主要危险因素,糖尿病脑缺血的患者住院时间更长,长期残疾风险更高且预后不良。小胶质细胞是脑内驻留的巨噬细胞,脑损伤后会发生表型和功能改变,对脑组织有损害和修复作用。小胶质细胞/巨噬细胞表型转变在糖尿病合并缺血性脑损伤中发挥重要作用。本文针对小胶质细胞/巨噬细胞极化与糖尿病合并缺血性脑损伤的研究进展作一综述。
关键词小胶质细胞/巨噬细胞    极化    糖尿病脑缺血    
Research progress of microglia/macrophage polarization in ischemic brain injury complicated with diabetes mellitus
AN Lulu, HAN Jiangquan, GUAN Jinfan, TIAN Mingqiao    
Department of Neurology, the Fifth Affiliated Hospital(Zhuhai) of Zunyi Medical University, Zhuhai 519100, China
Abstract: Diabete mellitus is one of the most important risk factors for brain death. Patients with diabetic cerebral ischemia need longer hospitalization and are at higher risk for long-term disability and poor prognosis. Microglia are macrophages that reside in the brain. Phenotypes and functions of microglia can be altered during brain damage, causing damage and repair of brain tissue. The phenotype transformation of microglia/macrophage plays a dominant role in diabetic patients with ischemic brain injury. This article reviews the research progress of microglia/macrophage polarization in ischemic brain injury complicated with diabetes mellitus.
Keywords: microglia/macrophage    polarization    diabetes cerebral ischemia    

调查数据显示,中风是目前导致中国居民死亡的首要原因,具有高发病率、高死亡率和高致残率的特点[1]。中风又称脑卒中,分为缺血性脑卒中和出血性脑卒中,缺血性脑卒中占80%,出血性脑卒中占20%,而在糖尿病患者中,出血性脑卒中比例反而减低,而缺血性脑卒中比例增加的更明显,在22个国家的病例对照研究中发现,相对于无糖尿病的患者,糖尿病患者发生中风的风险增加36%[2]。目前对于脑卒中最有效的治疗方法是重组织型纤溶酶原激活剂(rtPA)溶栓治疗和介入治疗,但由于其治疗时间窗窄、严重的并发症、费用高和设备条件问题限制了它们的临床使用[3]。因此,需要寻找和发现其他有效的治疗方法。研究发现,脑损伤时小胶质细胞/巨噬细胞被激活,极化成M1型小胶质细胞/巨噬细胞和M2型小胶质细胞/巨噬细胞,M2型通过神经发生、轴突再生、血管生成、少突胶质细胞生成和髓鞘再生促进大脑恢复,M1型损害神经发生并加重神经功能缺损[4]

1 糖尿病与缺血性脑卒中

糖尿病是一种与慢性高血糖相关的严重代谢性疾病,在缺血性脑损伤早期,高血糖会增加炎症反应、氧化应激、再灌注损伤等加重脑损害,使缺血性脑卒中的死亡率增加[2]。据最新统计,2017年糖尿病影响着全世界4.51亿人,到2045年约可增加至6.29亿人,其中2型糖尿病的患者占90%以上,大大增加缺血性脑卒中的风险,给家庭和社会带来了严重的负担[5]。与非糖尿病脑缺血患者相比,糖尿病合并脑缺血患者对rtPA的反应较差,并有较高的出血转化风险,住院时间更长、再入院次数增多[2, 3, 6]。Zhang等[7]研究证实,糖尿病会加剧大鼠海马神经血管的损伤,抑制大脑的重塑过程,使中风后的神经功能恢复受损和认知功能下降,加剧炎症反应。糖尿病加重缺血性脑损伤的机制,可能与炎症反应、胰岛素抵抗、线粒体功能障碍和氧化应激等有关[8]

2 小胶质细胞与巨噬细胞的关系

小胶质细胞作为脑内的主要免疫细胞,占中枢神经系统细胞的10%~15%[9]。从Rio-Hortega最早发现小胶质细胞时,它的起源一直备受争议,目前被大多数学者达成共识的是小胶质细胞主要来源于中胚层/间充质的祖细胞[10]。Florent Ginhoux等[11]通过体内谱系追踪显示,在整个胚胎发育过程中小胶质细胞的表型类似于卵黄囊巨噬细胞的表型,命运映射分析揭示了成年小胶质细胞衍生自原始巨噬细胞。小胶质细胞已被证实可以表达多种与巨噬细胞表面相同的标志物,如CSF-1、CD11b、F4/80、CX3CR1和lba-1等,而且二者还有介导炎症、进行免疫监测、清除细胞碎片等相似功能[12]。脑损伤时,由于缺乏高度特异性的标记物,大多数研究人员不区分小胶质细胞和巨噬细胞,而是将它们归为同一细胞群,即小胶质细胞/巨噬细胞[13]

3 中风后小胶质细胞/巨噬细胞极化与表型转化

缺血性脑卒中引起的脑损伤是由一系列在时间和空间上的病理生理变化发展而来,包括兴奋性毒性、氧化应激、炎症和细胞凋亡等[14]。其中,炎症反应涉及中风的所有阶段,包括早期的破环事件和大脑后期的组织修复。小胶质细胞作为中枢神经系统感染的第一道防线,当发生脑损伤时,在数分钟内激活,发生形态学的改变并向梗死灶聚集。脑内的小胶质细胞具有高度可塑性,可根据炎症微环境的变化分为M1和M2表型的过程称为极化。通常,用脂多糖和干扰素-γ进行体外刺激可诱导小胶质细胞成为释放破坏性促炎介质的“经典激活”的M1型;而用IL-4和IL-10可诱导其向具有神经保护特性的“替代激活”M2表型转化[15]。M1型的特点是高表达TNF-α、IL-1β、IL-6等促炎介质和基质金属蛋白酶9(MMP-9),可以引起神经元凋亡和血脑屏障破坏;相反,M2型分泌抗炎细胞因子,例如TGF-β、IL-4、IL-10,还可以分泌脑源性神经营养因子(BDNF)和血管内皮生长因子(VEGF)促进缺血性脑损伤后的轴突生长和血管生成[9]。在缺血性中风早期,小胶质细胞/巨噬细胞主要极化为M2型,第3天M2型会达高峰,随着时间的推移,在损伤区域逐渐转变成以M1型为主的表型[4]

众多因素参与了小胶质细胞极化的过程,如自噬、转录因子、离子通道蛋白、膜受体、基因表达调节剂等[9]。体内外实验证实,在中风模型中,予以大麻素、PPAR激动剂、类固醇激素、白介素、离子通道调节剂、二甲双胍和阿奇霉素等都可诱导小胶质细胞向M2表型极化[16]。研究发现,甲异靛和拟人参皂苷F11可通过减弱M1型小胶质细胞/巨噬细胞的炎性作用,增强M2型小胶质细胞/巨噬细胞的抗炎作用,减轻氧糖剥夺/复氧(OGD/R)诱导的神经元损伤[17-18]

4 糖尿病合并缺血性脑损伤后影响小胶质细胞/巨

噬细胞极化的因素炎症在糖尿病脑损伤中起着主要作用。当发生缺血性脑损伤时,糖尿病大鼠炎症介质表达增加,小胶质细胞和巨噬细胞活化加剧[19]。在db/db小鼠中风模型中,小胶质细胞/巨噬细胞表型更易向M1型转变,进而加剧脑结构的损害[20]。Darsalia等[21]研究显示,艾塞那肽(Exendin-4)可通过促进小胶质细胞/巨噬细胞向M2型极化,减轻缺血侧脑损伤。用载脂蛋白A-1模拟肽(D-4F)治疗可促进巨噬细胞向M2型转变,减少脑白质损伤和炎症因子表达,从而改善1型糖尿病合并脑缺血损伤大鼠的结局[22]。在糖尿病脑缺血大鼠中,Tribbles同源蛋白3(TRB3)可以通过下调PPAR-γ影响小胶质细胞/巨噬细胞极化[23]。予以迟发性人骨髓间充质干细胞(hMSC)治疗糖尿病脑缺血的大鼠会显著增加缺血侧脑中血小板衍生生长因子表达,减少促炎型M1巨噬细胞并增加抗炎型M2巨噬细胞[24]

5 糖尿病合并缺血性脑损伤后小胶质细胞/巨噬细胞极化的可能机制 5.1 核因子E2相关因子2/血红素加氧酶-1(Nrf2/HO-1)信号通路

Nrf2主要起到抗氧化应激和抗炎作用,Nrf2/HO-1信号通路已被证实对缺血性脑损伤有保护作用。Deng等[25]研究发现,在糖尿病脑缺血大鼠中,利拉鲁肽通过激活Nrf2/HO-1信号通路可减少缺血引起的脑损伤,减轻炎症反应。Luo等[26]发现,雷公藤素可通过激活Nrf2/HO-1信号通路诱导HO-1的表达从而抑制巨噬细胞向M1型极化,而HO-1的抑制剂Snpp减少了对M1型巨噬细胞极化的抑制作用。

5.2 Toll样受体4(TLR4)

缺血性脑损伤后,小胶质细胞、星形胶质细胞和内皮细胞中的Toll样受体4被激活并加剧炎症反应,通过抑制TLR4信号传导途径可以减少糖尿病合并缺血性脑损伤大鼠中的神经元凋亡,从而改善糖尿病脑缺血大鼠的神经功能缺损[27]。Tian等[28]研究发现,β-石竹烯(β-Caryophyllene)减轻了脂多糖诱导的神经炎症,下调了TLR4蛋白水平的表达,通过抑制TLR4途径促进了小胶质细胞向M2表型极化,从而预防缺血性脑卒中的发生。Abdul等[29]发现糖尿病合并缺血性脑损伤的大鼠会增加TLR4的表达,使得梗塞体积和水肿面积增大,加重神经功能缺损,抑制TLR4的激活可降低出血转换风险并促进神经功能恢复。

5.3 NLRP3炎性小体

当发生急性缺血性卒中时,会产生大量的损伤相关分子模式(DAMP),通过NF-κB和MAPK等多种信号途径,直接激活小胶质细胞/巨噬细胞中的炎症小体,导致血脑屏障破坏和白细胞浸润,加剧神经炎症反应[30]。NLRP3是细胞中的一种多蛋白复合物,是目前研究最广泛的炎症小体。NLRP3炎性小体通过多种途径上调胰岛和脂肪细胞中IL-1β的表达,加速T2DM的发展,NLRP3炎性小体的抑制剂MCC950可降低海马中活化的小胶质细胞数量,防止缺氧介导的BDNF分泌减少,从而减轻糖尿病合并脑缺血小鼠的神经功能缺损和提高存活率[31]。甲异靛可以通过抑制NLRP3炎性小体的活化进而调节小胶质细胞/巨噬细胞的极化来减轻脑部炎症[17]

6 展望

综上所述,小胶质细胞/巨噬细胞表型的转变对糖尿病合并缺血性脑损伤有着重要的作用。但有关小胶质细胞/巨噬细胞在糖尿病脑缺血中的作用机制尚未完全清楚,部分研究结果仍有争议,研究相关机制可以小胶质细胞/巨噬细胞从M1到M2的表型转换为治疗靶点,为糖尿病合并缺血性脑损伤提供新治疗策略。

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文章信息

安露露, 韩江全, 官劲帆, 田明巧
AN Lulu, HAN Jiangquan, GUAN Jinfan, TIAN Mingqiao
小胶质细胞/巨噬细胞极化对糖尿病合并缺血性脑损伤影响的研究进展
Research progress of microglia/macrophage polarization in ischemic brain injury complicated with diabetes mellitus
大连医科大学学报, 2020, 42(3): 258-261.
Journal of Dalian Medical University, 2020, 42(3): 258-261.
通信作者
韩江全, 教授。E-mail:gdshanjq@163.com.
基金项目
遵市科合社字(2018)20号

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