Chen Bo, Shi Guihong, Xu Jianye, Zhang Xu, Zhu Yanlin, Li Lei, Wang Cong, Gheyret Dilmurat, Wang Jinchao, Liu Xilei, Cao Yiyao, Tan Rui, Zhou Yuan, Jiang RongCai, Li Shenghui, Li Tuo, Liu Xiao, Chen Xin, Yang Guili, Zhang Jianning, Zhang Shu
Department of Neurosurgery, Tianjin Medical University General Hospital, Tianjin, 300052, China.
Key Laboratory of Post-Trauma Neuro-Repair and Regeneration in Central Nervous System, Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, State Key Laboratory of Experimental Hematology, Tianjin Neurological Institute, Ministry of Education, Tianjin, 300052, China.
Cell Commun Signal. 2025 Jul 1;23(1):317. doi: 10.1186/s12964-025-02319-4.
Traumatic brain injury (TBI) causes significant neuronal death, but the underlying mechanisms remain poorly understood. The role of interleukin-23 (IL-23) signaling in post-traumatic neuronal injury requires investigation.
We examined IL-23 levels in clinical samples from TBI patients and healthy controls. Using a mouse TBI model, we investigated the effects of IL-23 neutralization and explored the cellular mechanisms through analysis of IL-23 receptor expression, JAK2/STAT3 pathway activation, and macrophage infiltration.
We found elevated IL-23 levels in both serum and brain tissues of TBI patients. TBI induced neuronal IL-23 receptor expression and activated the JAK2/STAT3 pathway. Infiltrating macrophages were identified as the main IL-23 source, recruited by neuron-derived C-C motif chemokine ligand 2 (CCL2). IL-23 neutralization or CCL2 blockade reduced neuronal ferroptosis and improved neurological outcomes in the mouse model.
Our findings reveal a novel CCL2-macrophage-IL-23 axis in TBI pathogenesis, where IL-23 promotes neuronal ferroptosis through direct receptor-mediated effects. Targeting this pathway represents a potential therapeutic strategy for TBI treatment.
创伤性脑损伤（TBI）会导致大量神经元死亡，但其潜在机制仍知之甚少。白细胞介素-23（IL-23）信号在创伤后神经元损伤中的作用有待研究。
我们检测了TBI患者和健康对照者临床样本中的IL-23水平。使用小鼠TBI模型，我们研究了IL-23中和的作用，并通过分析IL-23受体表达、JAK2/STAT3通路激活和巨噬细胞浸润来探索细胞机制。
我们发现TBI患者的血清和脑组织中IL-23水平均升高。TBI诱导神经元IL-23受体表达并激活JAK2/STAT3通路。浸润的巨噬细胞被确定为主要的IL-23来源，由神经元衍生的C-C基序趋化因子配体2（CCL2）招募。在小鼠模型中，IL-23中和或CCL2阻断可减少神经元铁死亡并改善神经功能结局。
我们的研究结果揭示了TBI发病机制中一种新的CCL2-巨噬细胞-IL-23轴，其中IL-23通过直接受体介导的作用促进神经元铁死亡。靶向该通路代表了一种潜在的TBI治疗策略。
