Neutrophil-derived cathelicidin promotes cerebral angiogenesis after ischemic stroke
Neutrophil-derived cathelicidin promotes cerebral angiogenesis after ischemic stroke
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DOI：
10.1177/0271678x231175190
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发表时间：
2023-05
影响因子：
6.3
通讯作者：
Wanqing Xie;Tingting Huang;Yunlu Guo;Yueman Zhang;Weijie Chen;Yan Li;Chen Chen-Chen;Peiying Li
中科院分区：
文献类型：
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作者：
Wanqing Xie;Tingting Huang;Yunlu Guo;Yueman Zhang;Weijie Chen;Yan Li;Chen Chen-Chen;Peiying Li
中性粒细胞在缺血性脑卒中后脑损伤的演变中起关键作用。然而，它们如何影响中风后后期的大脑修复仍不确定。通过一项前瞻性临床卒中患者队列研究，我们发现卒中患者外周血中抗菌肽（CAMP）明显高于健康对照组。而在小鼠脑卒中模型中，CAMP在大脑中动脉闭塞（MCAO）后第1、3、7、14天外周血和脑缺血核心中均存在，且显著升高。在MCAO后7天和14天，CAMP - / -小鼠表现出明显的梗死体积增加，神经预后恶化，脑内皮细胞增殖和血管密度降低。利用缺氧葡萄糖剥夺（OGD）的bEND3细胞，我们发现重组CAMP肽（rCAMP）处理后血管生成相关基因的表达显著增加。脑室内注射CAMP受体CXCR2拮抗剂AZD-5069，或shCXCR2重组腺相关病毒（rAAV）抑制CXCR2，会阻碍MCAO后血管生成和神经系统恢复。给予rCAMP促进内皮细胞增殖和血管生成，并减轻MCAO后14天的神经功能缺损。综上所述，中性粒细胞源性CAMP是促进脑卒中后血管生成和脑卒中后期神经功能恢复的重要介质。
Neutrophils play critical roles in the evolving of brain injuries following ischemic stroke. However, how they impact the brain repair in the late phase after stroke remain uncertain. Using a prospective clinical stroke patient cohort, we found significantly increased cathelicidin antimicrobial peptide (CAMP) in the peripheral blood of stroke patients compared to that of healthy controls. While in the mouse stroke model, CAMP was present in the peripheral blood, brain ischemic core and significantly increased at day 1, 3, 7, 14 after middle cerebral artery occlusion (MCAO). CAMP−/− mice exhibited significantly increased infarct volume, exacerbated neurological outcome, reduced cerebral endothelial cell proliferation and vascular density at 7 and 14 days after MCAO. Using bEND3 cells subjected to oxygen-glucose deprivation (OGD), we found significantly increased angiogenesis-related gene expression with the treatment of recombinant CAMP peptide (rCAMP) after reoxygenation. Intracerebroventricular injection (ICV) of AZD-5069, the antagonist of CAMP receptor CXCR2, or knockdown of CXCR2 by shCXCR2 recombinant adeno-associated virus (rAAV) impeded angiogenesis and neurological recovery after MCAO. Administration of rCAMP promoted endothelial proliferation and angiogenesis and attenuated neurological deficits 14 days after MCAO. In conclusion, neutrophil derived CAMP represents an important mediator that could promote post-stroke angiogenesis and neurological recovery in the late phase after stroke.