Microglia exacerbate white matter injury via complement C3/C3aR pathway after hypoperfusion
Microglia exacerbate white matter injury via complement C3/C3aR pathway after hypoperfusion
复制标题
低灌注后小胶质细胞通过补体 C3/C3aR 途径加剧白质损伤
DOI：
10.7150/thno.35841
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发表时间：
2020
期刊：
影响因子：
12.4
通讯作者：
Yang Guo-Yuan
中科院分区：
文献类型：
--
作者：
Zhang Lin-Yuan;Pan Jiaji;Mamtilahun Muyassar;Zhu Yuan;Wang Liping;Venkatesh Ashwin;Shi Rubing;Tu Xuanqiang;Jin Kunlin;Wang Yongting;Zhang Zhijun;Yang Guo-Yuan
小胶质细胞活化参与脑低灌注后白色物质损伤。然而，其潜在机制尚不清楚。在此，我们探讨激活的小胶质细胞是否通过补体C3-C3 aR途径加重慢性脑低灌注后的白色损伤。方法：成年雄性Sprague-Dawley大鼠（n = 80）进行双侧颈总动脉闭塞7，14和28天。同步辐射血管造影和三维动脉自旋标记检测脑血管密度和血流量。进行神经行为评估、脑功能成像和免疫组织化学以评价小胶质细胞和C3-C3 aR通路的活化。此外，使用C3 aR敲除小鼠来建立C3-C3 aR信号传导对低灌注后小胶质细胞活化和白色损伤的因果关系。结果：低灌注后脑血管密度和血流量明显降低（P<0.05）。空间学习记忆障碍和白色质损害（P<0.05）。这些损伤与低灌注组中异常的小胶质细胞活化以及粘附和吞噬髓鞘的反应性小胶质细胞数量的增加相关（p<0.05），这伴随着补体C3及其受体C3 aR的上调（p<0.05）。C3 ar 1基因缺失可显著抑制小胶质细胞的异常活化，逆转低灌注后的白色损伤（p<0.05）。此外，C3 α R拮抗剂SB 290157减少了粘附于髓鞘的小胶质细胞的数量（p<0.05），减轻了慢性低灌注大鼠的白色损伤和认知缺陷（p<0.05）。结论：我们的研究结果表明，在慢性低灌注时，异常激活的小胶质细胞通过C3-C3 aR通路加重了白色损伤。这些发现表明C3 aR在通过异常小胶质细胞激活介导神经炎症和白色物质损伤中发挥关键作用，这为小血管疾病和血管性痴呆提供了新的治疗靶点。
Microglial activation participates in white matter injury after cerebral hypoperfusion. However, the underlying mechanism is unclear. Here, we explore whether activated microglia aggravate white matter injury via complement C3-C3aR pathway after chronic cerebral hypoperfusion. Methods: Adult male Sprague-Dawley rats (n = 80) underwent bilateral common carotid artery occlusion for 7, 14, and 28 days. Cerebral vessel density and blood flow were examined by synchrotron radiation angiography and three-dimensional arterial spin labeling. Neurobehavioral assessments, CLARITY imaging, and immunohistochemistry were performed to evaluate activation of microglia and C3-C3aR pathway. Furthermore, C3aR knockout mice were used to establish the causal relationship of C3-C3aR signaling on microglia activation and white matter injury after hypoperfusion. Results: Cerebral vessel density and blood flow were reduced after hypoperfusion (p<0.05). Spatial learning and memory deficits and white matter injury were shown (p<0.05). These impairments were correlated with aberrant microglia activation and an increase in the number of reactive microglia adhering to and phagocytosed myelin in the hypoperfusion group (p<0.05), which were accompanied by the up-regulation of complement C3 and its receptors C3aR (p<0.05). Genetic deletion of C3ar1 significantly inhibited aberrant microglial activation and reversed white matter injury after hypoperfusion (p<0.05). Furthermore, the C3aR antagonist SB290157 decreased the number of microglia adhering to myelin (p<0.05), attenuated white matter injury and cognitive deficits in chronic hypoperfusion rats (p<0.05). Conclusions: Our results demonstrated that aberrant activated microglia aggravate white matter injury via C3-C3aR pathway during chronic hypoperfusion. These findings indicate C3aR plays a critical role in mediating neuroinflammation and white matter injury through aberrant microglia activation, which provides a novel therapeutic target for the small vessel disease and vascular dementia.