外伤性脑损伤中中性粒细胞胞外陷阱诱导内皮损伤,加重血管痉挛。

IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Theranostics Pub Date : 2025-08-16 eCollection Date: 2025-01-01 DOI:10.7150/thno.115746
Jinchao Wang, Lei Li, Jianye Xu, Dilmurat Gheyret, Kaiji Li, Xu Zhang, Haoran Jia, Ye Tian, Xiao Liu, Shenghui Li, Guili Yang, Yalong Gao, Ruilong Peng, Huajie Liu, Bin Liu, Jianfeng Zhuang, Cong Wang, Xin Chen, Yafan Liu, Bo Chen, Chuan Huang, Yuhan Li, Xin Chen, Jianning Zhang, Shu Zhang
{"title":"外伤性脑损伤中中性粒细胞胞外陷阱诱导内皮损伤,加重血管痉挛。","authors":"Jinchao Wang, Lei Li, Jianye Xu, Dilmurat Gheyret, Kaiji Li, Xu Zhang, Haoran Jia, Ye Tian, Xiao Liu, Shenghui Li, Guili Yang, Yalong Gao, Ruilong Peng, Huajie Liu, Bin Liu, Jianfeng Zhuang, Cong Wang, Xin Chen, Yafan Liu, Bo Chen, Chuan Huang, Yuhan Li, Xin Chen, Jianning Zhang, Shu Zhang","doi":"10.7150/thno.115746","DOIUrl":null,"url":null,"abstract":"<p><p>Cerebral vasospasm (CVS) critically exacerbates secondary brain injury following traumatic brain injury (TBI). Understanding the underlying mechanisms is essential for developing targeted interventions. <b>Methods:</b> We developed a comprehensive murine multimodal imaging platform to evaluate CVS cerebral perfusion, and blood-brain barrier (BBB) integrity, integrating <i>in vivo</i> multiphoton microscopy, magnetic resonance angiography, carotid Doppler ultrasound, and laser speckle contrast imaging with molecular assays and functional assessments. Additionally, we comprehensively analyze single-cell RNA (TBI vs Sham) and bulk-RNA data (NETs-treated vs Control), delineating NETs-driven endothelial injury signatures. Finally, we explored the roles of PAD4<sup>-/-</sup>, TLR4 inhibition and TREM1 blockade in blocking NETs-induced endothelial injury and CVS, validating key therapeutic targets. <b>Results:</b> Our findings reveal that neutrophil extracellular traps (NETs) stimulate endothelial cells, promoting intracellular accumulation of TREM1, which forms a stable complex with NF-κB. This complex synergistically amplifies TLR4-mediated inflammatory responses, constituting a novel mechanism by which NETs aggravate endothelial injury and vasospasm after TBI. Preclinical interventions aimed at inhibiting NET formation or blocking TREM1 signaling significantly reduced neuroinflammation, cerebral edema, and CVS. <b>Conclusions:</b> These findings identify TREM1 as a promising therapeutic target and illuminate a NET-driven crosstalk between vascular dysfunction and inflammatory cascades in the context of TBI, offering novel translational insights for mitigating secondary brain injury.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 17","pages":"9221-9239"},"PeriodicalIF":13.3000,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12439479/pdf/","citationCount":"0","resultStr":"{\"title\":\"Neutrophil extracellular traps induce endothelial damage and exacerbate vasospasm in traumatic brain injury.\",\"authors\":\"Jinchao Wang, Lei Li, Jianye Xu, Dilmurat Gheyret, Kaiji Li, Xu Zhang, Haoran Jia, Ye Tian, Xiao Liu, Shenghui Li, Guili Yang, Yalong Gao, Ruilong Peng, Huajie Liu, Bin Liu, Jianfeng Zhuang, Cong Wang, Xin Chen, Yafan Liu, Bo Chen, Chuan Huang, Yuhan Li, Xin Chen, Jianning Zhang, Shu Zhang\",\"doi\":\"10.7150/thno.115746\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Cerebral vasospasm (CVS) critically exacerbates secondary brain injury following traumatic brain injury (TBI). Understanding the underlying mechanisms is essential for developing targeted interventions. <b>Methods:</b> We developed a comprehensive murine multimodal imaging platform to evaluate CVS cerebral perfusion, and blood-brain barrier (BBB) integrity, integrating <i>in vivo</i> multiphoton microscopy, magnetic resonance angiography, carotid Doppler ultrasound, and laser speckle contrast imaging with molecular assays and functional assessments. Additionally, we comprehensively analyze single-cell RNA (TBI vs Sham) and bulk-RNA data (NETs-treated vs Control), delineating NETs-driven endothelial injury signatures. Finally, we explored the roles of PAD4<sup>-/-</sup>, TLR4 inhibition and TREM1 blockade in blocking NETs-induced endothelial injury and CVS, validating key therapeutic targets. <b>Results:</b> Our findings reveal that neutrophil extracellular traps (NETs) stimulate endothelial cells, promoting intracellular accumulation of TREM1, which forms a stable complex with NF-κB. This complex synergistically amplifies TLR4-mediated inflammatory responses, constituting a novel mechanism by which NETs aggravate endothelial injury and vasospasm after TBI. Preclinical interventions aimed at inhibiting NET formation or blocking TREM1 signaling significantly reduced neuroinflammation, cerebral edema, and CVS. <b>Conclusions:</b> These findings identify TREM1 as a promising therapeutic target and illuminate a NET-driven crosstalk between vascular dysfunction and inflammatory cascades in the context of TBI, offering novel translational insights for mitigating secondary brain injury.</p>\",\"PeriodicalId\":22932,\"journal\":{\"name\":\"Theranostics\",\"volume\":\"15 17\",\"pages\":\"9221-9239\"},\"PeriodicalIF\":13.3000,\"publicationDate\":\"2025-08-16\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12439479/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Theranostics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.7150/thno.115746\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q1\",\"JCRName\":\"MEDICINE, RESEARCH & EXPERIMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Theranostics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.7150/thno.115746","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
引用次数: 0

摘要

脑血管痉挛(CVS)严重加重创伤性脑损伤(TBI)后继发性脑损伤。了解潜在机制对于制定有针对性的干预措施至关重要。方法:我们开发了一个综合的小鼠多模态成像平台来评估CVS脑灌注和血脑屏障(BBB)的完整性,将体内多光子显微镜、磁共振血管造影、颈动脉多普勒超声和激光散斑对比成像与分子分析和功能评估相结合。此外,我们全面分析了单细胞RNA (TBI vs Sham)和大量RNA数据(nets处理vs对照组),描绘了nets驱动的内皮损伤特征。最后,我们探讨了PAD4-/-、TLR4抑制和TREM1阻断在阻断nets诱导的内皮损伤和CVS中的作用,验证了关键的治疗靶点。结果:我们的研究结果表明,中性粒细胞胞外陷阱(NETs)刺激内皮细胞,促进tre1在细胞内的积累,tre1与NF-κB形成稳定的复合物。该复合物协同放大tlr4介导的炎症反应,构成了NETs加重TBI后内皮损伤和血管痉挛的新机制。旨在抑制NET形成或阻断TREM1信号传导的临床前干预可显著降低神经炎症、脑水肿和CVS。结论:这些发现确定了TREM1是一个有希望的治疗靶点,并阐明了脑外伤背景下血管功能障碍和炎症级联反应之间net驱动的串音,为减轻继发性脑损伤提供了新的转化见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Neutrophil extracellular traps induce endothelial damage and exacerbate vasospasm in traumatic brain injury.

Cerebral vasospasm (CVS) critically exacerbates secondary brain injury following traumatic brain injury (TBI). Understanding the underlying mechanisms is essential for developing targeted interventions. Methods: We developed a comprehensive murine multimodal imaging platform to evaluate CVS cerebral perfusion, and blood-brain barrier (BBB) integrity, integrating in vivo multiphoton microscopy, magnetic resonance angiography, carotid Doppler ultrasound, and laser speckle contrast imaging with molecular assays and functional assessments. Additionally, we comprehensively analyze single-cell RNA (TBI vs Sham) and bulk-RNA data (NETs-treated vs Control), delineating NETs-driven endothelial injury signatures. Finally, we explored the roles of PAD4-/-, TLR4 inhibition and TREM1 blockade in blocking NETs-induced endothelial injury and CVS, validating key therapeutic targets. Results: Our findings reveal that neutrophil extracellular traps (NETs) stimulate endothelial cells, promoting intracellular accumulation of TREM1, which forms a stable complex with NF-κB. This complex synergistically amplifies TLR4-mediated inflammatory responses, constituting a novel mechanism by which NETs aggravate endothelial injury and vasospasm after TBI. Preclinical interventions aimed at inhibiting NET formation or blocking TREM1 signaling significantly reduced neuroinflammation, cerebral edema, and CVS. Conclusions: These findings identify TREM1 as a promising therapeutic target and illuminate a NET-driven crosstalk between vascular dysfunction and inflammatory cascades in the context of TBI, offering novel translational insights for mitigating secondary brain injury.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Theranostics
Theranostics MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
25.40
自引率
1.60%
发文量
433
审稿时长
1 months
期刊介绍: Theranostics serves as a pivotal platform for the exchange of clinical and scientific insights within the diagnostic and therapeutic molecular and nanomedicine community, along with allied professions engaged in integrating molecular imaging and therapy. As a multidisciplinary journal, Theranostics showcases innovative research articles spanning fields such as in vitro diagnostics and prognostics, in vivo molecular imaging, molecular therapeutics, image-guided therapy, biosensor technology, nanobiosensors, bioelectronics, system biology, translational medicine, point-of-care applications, and personalized medicine. Encouraging a broad spectrum of biomedical research with potential theranostic applications, the journal rigorously peer-reviews primary research, alongside publishing reviews, news, and commentary that aim to bridge the gap between the laboratory, clinic, and biotechnology industries.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信