Inhibition of S100A8/A9 ameliorates neuroinflammation by blocking NET formation following traumatic brain injury

IF 11.9 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Redox Biology Pub Date : 2025-02-05 DOI:10.1016/j.redox.2025.103532
Guihong Shi , Yiyao Cao , Jianye Xu , Bo Chen , Xu Zhang , Yanlin Zhu , Liang Liu , Xilei Liu , Luyuan Zhang , Yuan Zhou , Shenghui Li , Guili Yang , Xiao Liu , Fanglian Chen , Xin Chen , Jianning Zhang , Shu Zhang
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Abstract

Traumatic brain injury (TBI) triggers a robust inflammatory response that is closely linked to worsened clinical outcomes. S100A8/A9, also known as calprotectin or myeloid-related protein-8/14 (MRP8/14), is an alarmin primarily secreted by activated neutrophils with potent pro-inflammatory property. In this study, we explored the roles of S100A8/A9 in modulating neuroinflammation and influencing TBI outcomes, delving into the underlying mechanisms. S100A8/A9-enriched neutrophils were present in the injured brain tissue of TBI patients, and elevated plasma levels of S100A8/A9 were correlated with poorer neurological function. Furthermore, using a TBI mouse model, we demonstrated that treatment with the selective S100A8/A9 inhibitor Paquinimod significantly mitigated neuroinflammation and neuronal death, thereby improving the prognosis of TBI mice. Mechanistically, we found that S100A8/A9, in conjunction with neutrophil activation and infiltration into the brain, enhances reactive oxygen species (ROS) production within neutrophils, accelerating PAD4-mediated neutrophil extracellular trap (NET) formation, which in turn exacerbates neuroinflammation. These findings suggest that S100A8/A9 amplifies neuroinflammatory responses by promoting NET formation in neutrophils. Inhibition of S100A8/A9 effectively attenuated NET-mediated neuroinflammation; however, when PAD4 was overexpressed in the brain using adenovirus, leading to an increased formation of NET in the brain, the anti-inflammatory effects of S100A8/A9 inhibition were markedly diminished. Further experiments with PAD4 knockout mice confirmed that the reduction of NETs could substantially alleviate S100A8/A9-driven neuroinflammation. Finally, we established that the suppression of NET formation by S100A8/A9 inhibition is primarily mediated through the AMPK/Nrf2/HO-1 signaling pathway. These findings underscore the critical pathological role of S100A8/A9 in TBI and emphasize the need for further exploration of S100A8/A9 inhibitor Paquinimod as a potential therapeutic strategy for TBI.

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抑制S100A8/A9通过阻断创伤性脑损伤后NET的形成来改善神经炎症
创伤性脑损伤(TBI)引发强烈的炎症反应,与恶化的临床结果密切相关。S100A8/A9,也称为钙保护蛋白或髓细胞相关蛋白-8/14 (MRP8/14),是一种主要由活化的中性粒细胞分泌的报警蛋白,具有强效的促炎特性。在本研究中,我们探讨了S100A8/A9在调节神经炎症和影响TBI预后中的作用,并深入探讨了其潜在机制。TBI患者损伤脑组织中存在富含S100A8/A9的中性粒细胞,血浆中S100A8/A9水平升高与神经功能较差相关。此外,通过TBI小鼠模型,我们证明了使用选择性S100A8/A9抑制剂帕喹尼莫德治疗可显著减轻神经炎症和神经元死亡,从而改善TBI小鼠的预后。在机制上,我们发现S100A8/A9与中性粒细胞激活和渗入大脑一起,增强中性粒细胞内活性氧(ROS)的产生,加速pad4介导的中性粒细胞胞外陷阱(NET)的形成,从而加剧神经炎症。这些发现表明S100A8/A9通过促进中性粒细胞中NET的形成来放大神经炎症反应。抑制S100A8/A9可有效减轻神经网络介导的神经炎症;然而,当PAD4通过腺病毒在大脑中过度表达,导致大脑中NET的形成增加时,抑制S100A8/A9的抗炎作用显着减弱。进一步的PAD4敲除小鼠实验证实,NETs的减少可以显著减轻S100A8/ a9驱动的神经炎症。最后,我们发现S100A8/A9抑制NET的形成主要是通过AMPK/Nrf2/HO-1信号通路介导的。这些发现强调了S100A8/A9在TBI中的关键病理作用,并强调了进一步探索S100A8/A9抑制剂帕喹尼莫作为TBI潜在治疗策略的必要性。
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来源期刊
Redox Biology
Redox Biology BIOCHEMISTRY & MOLECULAR BIOLOGY-
CiteScore
19.90
自引率
3.50%
发文量
318
审稿时长
25 days
期刊介绍: Redox Biology is the official journal of the Society for Redox Biology and Medicine and the Society for Free Radical Research-Europe. It is also affiliated with the International Society for Free Radical Research (SFRRI). This journal serves as a platform for publishing pioneering research, innovative methods, and comprehensive review articles in the field of redox biology, encompassing both health and disease. Redox Biology welcomes various forms of contributions, including research articles (short or full communications), methods, mini-reviews, and commentaries. Through its diverse range of published content, Redox Biology aims to foster advancements and insights in the understanding of redox biology and its implications.
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