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

作者：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 · 发表于：Redox Biology · 年份：2025 · DOI：10.1016/j.redox.2025.103532 · 被引用次数：44 · 研究领域：S100 Proteins and Annexins、Traumatic Brain Injury and Neurovascular Disturbances、Neutrophil, Myeloperoxidase and Oxidative Mechanisms

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-infla...