Neutrophil Extracellular Traps Regulate Surgical Brain Injury by Activating the cGAS-STING Pathway

IF 3.6 4区 医学 Q3 CELL BIOLOGY
Bingbing Li, Lixia Xu, Zhengang Wang, Qi Shi, Yang Cui, Weijia Fan, Qiaoli Wu, Xiaoguang Tong, Hua Yan
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引用次数: 0

Abstract

Surgical brain injury (SBI), induced by neurosurgical procedures or instruments, has not attracted adequate attention. The pathophysiological process of SBI remains sparse compared to that of other central nervous system diseases thus far. Therefore, novel and effective therapies for SBI are urgently needed. In this study, we found that neutrophil extracellular traps (NETs) were present in the circulation and brain tissues of rats after SBI, which promoted neuroinflammation, cerebral edema, neuronal cell death, and aggravated neurological dysfunction. Inhibition of NETs formation by peptidylarginine deiminase (PAD) inhibitor or disruption of NETs with deoxyribonuclease I (DNase I) attenuated SBI-induced damages and improved the recovery of neurological function. We show that SBI triggered the activation of cyclic guanosine monophosphate–adenosine monophosphate synthase stimulator of interferon genes (cGAS-STING), and that inhibition of the cGAS-STING pathway could be beneficial. It is worth noting that DNase I markedly suppressed the activation of cGAS-STING, which was reversed by the cGAS product cyclic guanosine monophosphate–adenosine monophosphate (cGMP-AMP, cGAMP). Furthermore, the neuroprotective effect of DNase I in SBI was also abolished by cGAMP. NETs may participate in the pathophysiological regulation of SBI by acting through the cGAS-STING pathway. We also found that high-dose vitamin C administration could effectively inhibit the formation of NETs post-SBI. Thus, targeting NETs may provide a novel therapeutic strategy for SBI treatment, and high-dose vitamin C intervention may be a promising translational therapy with an excellent safety profile and low cost.

Graphical Abstract

The schematic diagram shows the formation of NETs activated cGAS-STING pathway after SBI, leading to increased microglia activation, accompanied with elevation of inflammatory factors, which in turn aggravated brain injury.

Abstract Image

中性粒细胞胞外陷阱通过激活 cGAS-STING 通路调控手术脑损伤
由神经外科手术或器械引起的外科脑损伤(SBI)尚未引起足够的重视。迄今为止,与其他中枢神经系统疾病相比,SBI 的病理生理学过程仍然十分稀少。因此,亟需针对 SBI 的新型有效疗法。在这项研究中,我们发现中性粒细胞胞外陷阱(NETs)存在于 SBI 后大鼠的血液循环和脑组织中,促进了神经炎症、脑水肿、神经细胞死亡并加重了神经功能障碍。用肽基精氨酸脱氨酶(PAD)抑制剂抑制 NETs 的形成,或用脱氧核糖核酸酶 I(DNase I)破坏 NETs,可减轻 SBI 引起的损伤,改善神经功能的恢复。我们的研究表明,SBI 触发了环磷酸鸟苷-单磷酸腺苷合成酶干扰素基因刺激器(cGAS-STING)的激活,而抑制 cGAS-STING 通路可能是有益的。值得注意的是,DNase I 能明显抑制 cGAS-STING 的激活,而 cGAS 产物环磷酸鸟苷-单磷酸腺苷(cGMP-AMP,cGAMP)能逆转这种激活。此外,在 SBI 中 DNase I 的神经保护作用也被 cGAMP 削弱。NETs可能通过cGAS-STING途径参与SBI的病理生理调控。我们还发现,大剂量服用维生素 C 能有效抑制 SBI 后 NET 的形成。因此,靶向NETs可能为SBI治疗提供了一种新的治疗策略,而大剂量维生素C干预可能是一种具有良好安全性和低成本的有前景的转化疗法。图解摘要示意图显示,SBI后NETs的形成激活了cGAS-STING通路,导致小胶质细胞活化增加,并伴有炎症因子升高,进而加重了脑损伤。
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来源期刊
CiteScore
7.70
自引率
0.00%
发文量
137
审稿时长
4-8 weeks
期刊介绍: Cellular and Molecular Neurobiology publishes original research concerned with the analysis of neuronal and brain function at the cellular and subcellular levels. The journal offers timely, peer-reviewed articles that describe anatomic, genetic, physiologic, pharmacologic, and biochemical approaches to the study of neuronal function and the analysis of elementary mechanisms. Studies are presented on isolated mammalian tissues and intact animals, with investigations aimed at the molecular mechanisms or neuronal responses at the level of single cells. Cellular and Molecular Neurobiology also presents studies of the effects of neurons on other organ systems, such as analysis of the electrical or biochemical response to neurotransmitters or neurohormones on smooth muscle or gland cells.
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