Inhibition of S100A8/A9 ameliorates neuroinflammation by blocking NET formation following traumatic brain injury
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
Affiliations
Guihong Shi
Department of Neurosurgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang, China; Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China; Tianjin Neurological Institute, Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin, 300052, China
Yiyao Cao
Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China; Tianjin Neurological Institute, Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin, 300052, China
Jianye Xu
Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China; Tianjin Neurological Institute, Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin, 300052, China
Bo Chen
Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China; Tianjin Neurological Institute, Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin, 300052, China
Xu Zhang
School of Medicine, Nankai University, Tianjin, 300052, China
Yanlin Zhu
Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China; Tianjin Neurological Institute, Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin, 300052, China
Liang Liu
Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China; Tianjin Neurological Institute, Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin, 300052, China
Xilei Liu
Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China; Tianjin Neurological Institute, Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin, 300052, China
Luyuan Zhang
Department of Neurosurgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang, China
Yuan Zhou
Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China; Tianjin Neurological Institute, Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin, 300052, China
Shenghui Li
Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China; Tianjin Neurological Institute, Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin, 300052, China
Guili Yang
Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China; Tianjin Neurological Institute, Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin, 300052, China
Xiao Liu
Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China; Tianjin Neurological Institute, Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin, 300052, China
Fanglian Chen
Tianjin Neurological Institute, Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin, 300052, China
Xin Chen
Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China; Tianjin Neurological Institute, Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin, 300052, China
Jianning Zhang
Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China; Tianjin Neurological Institute, Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin, 300052, China; Corresponding author. at Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China.
Shu Zhang
Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China; Tianjin Neurological Institute, Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin, 300052, China; Corresponding author. Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin 300052, China:
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.
