Wang Jinchao, Li Lei, Xu Jianye, Gheyret Dilmurat, Li Kaiji, Zhang Xu, Jia Haoran, Tian Ye, Liu Xiao, Li Shenghui, Yang Guili, Gao Yalong, Peng Ruilong, Liu Huajie, Liu Bin, Zhuang Jianfeng, Wang Cong, Chen Xin, Liu Yafan, Chen Bo, Huang Chuan, Li Yuhan, Chen Xin, Zhang Jianning, Zhang Shu
Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, China.
National Key Laboratory of Post-Trauma Neuro-Repair and Regeneration in Central Nervous System, Tianjin Key Laboratory of Injuries, Variations, and Regeneration of Nervous System, Tianjin Neurological Institute, Ministry of Education, Tianjin, China.
Theranostics. 2025 Aug 16;15(17):9221-9239. doi: 10.7150/thno.115746. eCollection 2025.
Cerebral vasospasm (CVS) critically exacerbates secondary brain injury following traumatic brain injury (TBI). Understanding the underlying mechanisms is essential for developing targeted interventions. We developed a comprehensive murine multimodal imaging platform to evaluate CVS cerebral perfusion, and blood-brain barrier (BBB) integrity, integrating 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. 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. 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.
脑血管痉挛（CVS）严重加剧创伤性脑损伤（TBI）后的继发性脑损伤。了解其潜在机制对于开发针对性干预措施至关重要。我们开发了一个全面的小鼠多模态成像平台，以评估CVS的脑灌注和血脑屏障（BBB）完整性，该平台整合了多光子显微镜、磁共振血管造影、颈动脉多普勒超声和激光散斑对比成像，并结合分子检测和功能评估。此外，我们全面分析了单细胞RNA（TBI组与假手术组）和大量RNA数据（NETs处理组与对照组），描绘了NETs驱动的内皮细胞损伤特征。最后，我们探讨了PAD4、TLR4抑制和TREM1阻断在阻断NETs诱导的内皮细胞损伤和CVS中的作用，验证了关键治疗靶点。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TREM1在细胞内积累，TREM1与NF-κB形成稳定复合物。该复合物协同放大TLR4介导的炎症反应，构成了NETs加重TBI后内皮细胞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措施显著减轻了神经炎症、脑水肿和CVS。这些研究结果确定TREM1是一个有前景的治疗靶点，并揭示了TBI背景下NETs驱动的血管功能障碍与炎症级联反应之间的相互作用，为减轻继发性脑损伤提供了新的转化见解。
