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中华脑血管病杂志(电子版) ›› 2024, Vol. 18 ›› Issue (04) : 382 -392. doi: 10.11817/j.issn.1673-9248.2024.04.015

综述

补体在缺血性卒中疾病中的研究进展
唐欣1, 翟文海1, 王润婷1, 周胜宇1, 靳航1,†()   
  1. 1. 130021　吉林长春，吉林大学第一医院神经内科
  • 收稿日期:2023-11-27 出版日期:2024-08-01
  • 通信作者: 靳航
  • 基金资助:
    吉林省科技发展计划项目(YDZJ202301ZYTS505)

Research progress on the role of complement in ischemic stroke

Xin Tang1, Wenhai Zhai1, Runting Wang1, Shengyu Zhou1, Hang Jin1,†()   

  1. 1. Department of Neurology, the First Hospital of Jilin University, Changchun 130021, China
  • Received:2023-11-27 Published:2024-08-01
  • Corresponding author: Hang Jin
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唐欣, 翟文海, 王润婷, 周胜宇, 靳航. 补体在缺血性卒中疾病中的研究进展[J]. 中华脑血管病杂志(电子版), 2024, 18(04): 382-392.

Xin Tang, Wenhai Zhai, Runting Wang, Shengyu Zhou, Hang Jin. Research progress on the role of complement in ischemic stroke[J]. Chinese Journal of Cerebrovascular Diseases(Electronic Edition), 2024, 18(04): 382-392.

缺血性卒中发病率和致残率高，缺少除再灌注治疗之外的能有效减少神经功能缺损的措施。补体系统蛋白参与缺血性卒中相关的炎症反应。补体的表达受缺血性卒中不同时期的影响。补体第1成分q（C1q）对缺血性卒中的发生具有一定的预测价值，可能与其对动脉粥样硬化的调节有关。补体系统蛋白参与动脉血栓形成可能导致血栓栓塞性事件的发生。C1q、甘露糖结合凝集素（MBL）、补体（C）3和膜攻击复合物（MAC）的血清浓度与缺血性卒中导致的神经功能缺损的严重程度相关，其中高水平MBL、C3、MAC提示缺血性卒中预后不良。补体参与脑缺血再灌注损伤并与卒中后认知障碍有关。C3和C5对卒中后功能恢复具有双重作用。C4对评估合并糖尿病的卒中病情更有意义。目前基础实验研究多通过调节补体受体的表达来治疗缺血性脑损伤。本文主要综述了近五年补体系统蛋白在缺血性卒中疾病中的发病机制和评估卒中严重程度及预后中的研究，以期为缺血性卒中自起病到远期预后过程中的治疗提供思路。

关键词: 补体系统蛋白, 缺血性卒中, 动脉粥样硬化, 血栓形成, 神经功能缺损

Ischemic stroke presents significant morbidity and disability, with limited therapeutic options beyond reperfusion therapy to effectively reduce neurologic deficits. The inflammatory response associated with ischemic stroke involves the complement system proteins. The expression of complement is temporally influenced during distinct phases of ischemic stroke. Complement component 1q (C1q) demonstrates a discernable predictive value in relation to the onset of ischemic stroke, potentially attributable to its regulatory impact on atherosclerosis. Complement system proteins implicated in arterial thrombosis pose a risk of precipitating thromboembolic events. The serum concentrations of C1q, mannose-binding lectin (MBL), complement 3 (C3), and membrane attack complex (MAC) exhibit correlations with the severity of neurologic deficits resulting from ischemic stroke. Elevated levels of MBL, C3, and MAC are indicative of a less favorable prognosis in ischemic stroke cases. Complement plays a role in cerebral ischemia-reperfusion injury and is associated with post-stroke cognitive impairment. Both C3 and complement 5 (C5) exert a dual effect on functional recovery following stroke. Complement 4 (C4) proves to be more clinically informative in evaluating strokes occurring in the context of diabetes. Currently, the majority of foundational experimental studies focus on the treatment of ischemic brain injury through the modulation of complement receptor expression. This article reviews the research on the pathogenesis of ischemic stroke and the evaluation of stroke severity and prognosis in the past five years, in order to provide ideas for the treatment of ischemic stroke from onset to long-term prognosis.

Key words: Complement system proteins, Ischemic stroke, Atherosclerosis, Thrombosis, Neurologic deficits
图1 补体激活的主要途径及主要补体（C）成分 注：C1q为补体第1成分q，C1r为补体第1成分r，C1s为补体第1成分s，MBL为甘露糖结合凝集素，MASP为人甘露聚糖结合凝集素丝氨酸肽酶
表1 补体在脑缺血不同时间段水平的变化
补体种类 主要研究对象 采集时间 较正常范围或对照组 文献
C1q亚组分亚基B和C1r亚组分 参加健康检查的患者 缺血性卒中发作前7.3±4.4年 升高 [16]
C1q 2型糖尿病患者 AIS发病后48 h内 升高 [23]
AIS患者 AIS发病后7 d内 升高 [31]
MBL AIS患者 AIS发病后2 d内 升高 [18]
MBL-A 短暂MCAO小鼠模型 缺血后24 h 升高 [25]
MBL-C 短暂MCAO小鼠模型 缺血后48 h 升高 [25]
C4 AIS患者 AIS发病后3~4 d 降低 [19]
糖尿病患者 AIS患者入院后第2天 升高 [24]
维持性血液透析的患者 血液透析治疗5年时 升高 [17]
C3 首次AIS患者 AIS发病后2 d内 升高 [20]
AIS患者 AIS发病后3 d内 升高 [21]
AIS患者 AIS发病后3~4 d 升高 [19]
MCAO/R小鼠模型 术后0、6、12和24 h 升高 [26]
短暂MCAO糖尿病小鼠模型 缺血1 h后再灌注开始后2、6、12和 24 h 升高 [27]
短暂MCAO小鼠模型 缺血再灌注损伤24 h后 升高 [28]
C3a 二血管阻塞慢性脑缺血大鼠模型 术后7、14、28 d 术后7 d为升高峰值 [29]
栓塞性MCAO小鼠模型 术后6 h 升高 [30]
C3b 短暂MCAO小鼠模型 术后6、24、48、96 h，7 d 术后48 h为升高峰值 [32]
短暂MCAO小鼠模型 缺血1 h再灌注72 h后 升高 [28]
MAC AIS患者 AIS发病后72 h内 升高 [22]
表2 补体治疗在脑缺血实验模型中的应用
干预措施 主要作用机制 结局 模型类型 文献
C1INH 抑制补体经典途径、凝集素途径。减少损伤部位C3b沉积，降低Toll样受体2的水平 好转 局灶性脑缺血再灌注小鼠模型 [28]
重组人C1INH 抑制补体凝集素途径。减少C4b，抑制MBL-A和MBL-C依赖性信号 好转 短暂MCAO/R小鼠模型 [106]
RLS-0071 抑制补体经典途径。介导局部C1q水平的变化 好转 HIE大鼠模型 [108]
B4Crry 抑制C3、C3a、C5a和MAC的产生，抑制小胶质细胞活化 好转 小鼠栓塞性卒中后使用t-PA溶栓 [72]
抑制经典途径和旁路途径。抑制C1q、因子B和C3的表达，促进补体抑制剂CD55和抗凋亡Bcl-2基因的表达，抑制干扰素γ、干扰素调节因子、核因子-κB、STAT3表达，抑制小胶质细胞活化 好转 OGD/R体外模型，MCAO/R小鼠模型 [101]
治疗性低温 抑制补体经典途径。抑制系统性C1q、C5a的表达，抑制小胶质细胞C1q的表达，减少小胶质细胞和神经元中C3和C9的沉积，抑制凋亡细胞上C1q的结合 好转 HIE大鼠模型 [112]
内皮祖细胞移植 抑制C3/C3aR通路。抑制星形胶质细胞来源的C3和C3aR表达 好转 短暂MCAO小鼠模型 [107]
SB290157 减少血管细胞黏附分子1、ICAM-1、E-选择素和P-选择素，减少中性粒细胞黏附 好转 OGD/R体外模型 [113]
抑制小胶质细胞活化和小胶质细胞重新分配到髓磷脂 好转 二血管阻塞慢性脑缺血大鼠模型 [29]
抑制小胶质细胞的炎症形态变化 好转 MCAO小鼠模型 [102]
抑制内皮细胞中ICAM-1、环氧化酶2、还原型辅酶Ⅱ和锰超氧化物歧化酶，抑制ERK的激活，抑制氧化应激，利于恢复内皮细胞的紧密连接 好转 OGD体外模型 [42]
DF3016A 抑制C5a受体转录，抑制促炎细胞因子过表达，抑制微小RNA-181a过表达 好转 OGD/R体外模型 [114]
抑制微小RNA-132表达，提高BDNF水平 好转 OGD/R体外模型 [111]
PMX53 选择性抑制C5a受体，降低肿瘤坏死因子-α、白介素-1β、白介素-6水平，抑制TLR4/NF-κB 好转 MCAO/R大鼠模型，OGD/R体外模型 [107，110]
CR2fH 抑制补体受体2，抑制补体旁路途径。降低肿瘤坏死因子-α并升高BDNF水平。减少星形胶质细胞瘢痕形成 好转 短暂MCAO小鼠模型 [103]
抑制补体旁路途径 好转 小鼠栓塞性卒中后使用t-PA溶栓 [103]
抗CD11b mAb 抑制补体受体3（CR3），削弱小胶质细胞吞噬髓鞘碎片的能力 恶化 体内永久性MCAO模型 [115]
LA-1 激动CR3，增加突触素和突触后致密蛋白-95的表达 好转 短暂MCAO小鼠模型 [116]
远隔缺血处理 激活补体经典途径，上调补体 C3、C4b结合蛋白β链亚型X2、补体 C1s 亚组分 好转 MCAO成年恒河猴模型 [117]
图2 补体治疗作用靶点。本图展示了缺血性卒中实验模型中干预措施对补体系统的影响 注：C为补体，R为受体，C1q为补体第1成分q，C1r为补体第1成分r，C1s为补体第1成分s，MBL为甘露糖结合凝集素，MASP为人甘露聚糖结合凝集素丝氨酸肽酶，gC1qR为补体C1q结合蛋白，C1INH为C1酯酶抑制剂，RLS-0071为双作用补体抑制剂，B4Crry为损伤部位靶向C3抑制剂，TH为治疗性低温，EPC为内皮祖细胞，RIC为远隔缺血处理，SB290157为C3a受体拮抗剂，PMX53和DF3016A为选择性C5a受体抑制剂，CR2fH为补体受体2拮抗剂，抗CD11b mAb为抗CD11b单克隆抗体，LA-1为补体受体3激动剂
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