IL-23 promotes neuronal ferroptosis via IL-23R/STAT3 signaling after traumatic brain injury
Bo Chen, Guihong Shi, Jianye Xu, Xu Zhang, Yanlin Zhu, Lei Li, Cong Wang, Dilmurat Gheyret, Jinchao Wang, Xilei Liu, Yiyao Cao, Rui Tan, Yuan Zhou, Rongcai Jiang, Shenghui Li, Tuo Li, Xiao Liu, Xin Chen, Guili Yang, Jianning Zhang, Shu Zhang
Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.