抑制CCL/CXCL信号介导的中性粒细胞趋化减轻创伤性脑损伤后继发脑损伤  

Inhibition of CCL/CXCL signaling pathway-mediated neutrophil chemotaxis alleviates secondary brain injury after traumatic brain injury

作　　者：李凯璐 董宝文 彭涛 孟锦媛 冯达云 LI Kailu;DONG Baowen;PENG Tao;MENG Jinyuan;FENG Dayun(Xi'an Medical University,Xi'an 710021,China;Department of Neurosurgery,Tangdu Hospital,Air Force Medical University,Xi'an 710038,China;College of Life Sciences,Northwest University,Xi'an 710069,China)

机构地区：[1]西安医学院,陕西西安710021 [2]空军军医大学唐都医院神经外科,陕西西安710038 [3]西北大学生命科学学院,陕西西安710069

出　　处：《空军军医大学学报》2024年第12期1399-1405,共7页Journal of Air Force Medical University

基　　金：国家自然科学基金面上项目(82271318)。

摘　　要：目的探讨创伤性脑损伤(TBI)后外周中性粒细胞中枢趋化的机制及在继发脑损伤中的作用。方法在TBI后急性期6、12、24、48和72 h时间点动态采集TBI小鼠皮层损伤灶组织样本,通过转录组测序(RNA-seq)分析TBI后基因表达的动态变化及与外周免疫细胞趋化的相关性,并通过原代中性粒细胞与TBI模型验证CCL/CXCL信号在中性粒细胞趋化及对TBI后神经炎症的作用。结果RNA-seq结果显示,TBI后白细胞迁移、细胞因子介导的炎症等相关通路随时间显著上调,趋化因子CCL/CXCL家族基因以及促炎症因子基因在所有时间点共同上调。进一步证实CCL3、CCL6、CCL9、CXCL2和CXCL3可通过作用于CCR1和CXCR2受体,发挥趋化外周中性粒细胞进入中枢,并激活中性粒细胞炎症反应的作用(P<0.05,P<0.01)。药理学抑制CCR1和CXCR2可显著减轻TBI小鼠脑内中性粒细胞浸润、小胶质细胞激活和血脑屏障破坏。结论TBI后CCL/CXCL信号通路介导外周中性粒细胞向中枢趋化,可作为TBI后继发脑损伤的干预靶点。Objective To investigate the mechanisms underlying peripheral neutrophil central chemotaxis following traumatic brain injury(TBI)and its role in secondary brain injury.Methods Tissue samples from cortical lesions of TBI mice were dynamically collected at 6,12,24,48,and 72 h in the acute stage after TBI.RNA sequencing(RNA-seq)was used to analyze the dynamic changes of gene expression after TBI and the correlation with chemotaxis of peripheral immune cells.Primary neutrophils and TBI models were utilized to validate the role of CCL/CXCL signaling in neutrophil chemotaxis and neuroinflammation following TBI.Results The results of RNA-seq revealed significant upregulation over time of pathways related to leukocyte migration and cytokine-mediated inflammation after TBI.CCL/CXCL chemokine family genes as well as pro-inflammatory genes were upregulated across all time points.It was further confirmed that CCL3,CCL6,CCL9,CXCL2,and CXCL3 facilitated the recruitment of peripheral neutrophils into the central nervous system by acting on CCR1 and CXCR2 receptors,thereby activating inflammatory responses in neutrophils(P<0.05,P<0.01).Pharmacological inhibition of CCR1 and CXCR2 significantly mitigated neutrophil infiltration,microglial activation,and blood-brain barrier disruption in TBI mice.Conclusion The CCL/CXCL signaling pathway mediates the central chemotaxis of peripheral neutrophils following TBI,which can be used as an intervention target for secondary brain injury after TBI.

关 键 词：创伤性脑损伤 继发脑损伤 中性粒细胞 炎症反应 趋化因子 

分 类 号：R651.15[医药卫生—外科学]