C5a-C5AR1 axis as a potential trigger of the rupture of intracranial aneurysms

Subarachnoid hemorrhage due to rupture of intracranial aneurysm (IA) still has poor prognosis once after the onset in spite of modern technical advancement in medical care. The development of the novel therapeutic strategy based on molecular machineries regulating the rupture is thus mandatory for social health. Here, recent studies have clarified the potential role of neutrophil-mediated inflammatory responses in the process leading to rupture. Thereby, factors mediating the recruitment of neutrophils in situ could be the therapeutic targets to prevent rupture of IAs. In the present study, complement C5a receptor 1 (C5AR1) was picked up as the candidates from comprehensive gene expression profile data. The induction of C5AR1 in IA lesions exclusively in rupture-prone or ruptured lesions was then confirmed in immunohistochemistry. The ligand of C5AR1, C5a, was induced through the enzymatic digestion by tissue-type Plasminogen Activator and, intriguingly, forms the auto-amplification in C5a-C5AR1 axis to exacerbate neutrophil infiltration and resultant neutrophil-mediated inflammation in situ, which triggers rupture of IAs. In conclusion, we have, in the present study, examined potential factors mediating the infiltration of neutrophils into IA lesions and then identified C5a-C5AR1 axis. This cascade could become the therapeutic target to prevent rupture of IAs.尽管当前医疗技术已取得长足进步，但颅内动脉瘤（intracranial aneurysm, IA）破裂引发的蛛网膜下腔出血，在发病后仍预后不佳。因此，基于调控动脉瘤破裂的分子机制开发新型治疗策略，对公共卫生而言至关重要。近期已有研究阐明，中性粒细胞介导的炎症反应在动脉瘤破裂的发生过程中发挥潜在作用。据此，介导中性粒细胞向病变局部募集的相关因子，或可成为预防颅内动脉瘤破裂的治疗靶点。本研究借助综合基因表达谱数据，筛选出补体C5a受体1（complement C5a receptor 1, C5AR1）作为候选靶点。随后通过免疫组化实验证实，补体C5a受体1仅在易破裂或已破裂的颅内动脉瘤病变中表达上调。补体C5a受体1的配体——补体C5a（complement C5a），可经组织型纤溶酶原激活剂的酶解作用产生；有趣的是，C5a-C5a受体1信号轴可形成自扩增环路，加剧中性粒细胞向病变局部的浸润以及由此引发的中性粒细胞介导的炎症反应，进而触发颅内动脉瘤破裂。综上，本研究探讨了介导中性粒细胞向颅内动脉瘤病变浸润的潜在因子，并明确了C5a-C5a受体1信号轴。该级联反应或可成为预防颅内动脉瘤破裂的治疗靶点。