IL-23 promotes neuronal ferroptosis via IL-23R/STAT3 signaling after traumatic brain injury.

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.