Macrophages dying from ferroptosis promote microglia-mediated inflammatory responses during spinal cord injury.

The neurological deficits following traumatic spinal cord injury are associated with severe patient disability and economic consequences. Currently, an increasing number of studies are focusing on the importance of ferroptosis during acute organ injuries. However, the spatial and temporal distribution patterns of ferroptosis during SCI and the details of its role are largely unknown. In this study, in vivo experiments revealed that microglia are in close proximity to macrophages, the major cell type that undergoes ferroptosis following SCI. Furthermore, we found that ferroptotic macrophages aggravate SCI by inducing the proinflammatory properties of microglia. In vitro studies further revealed ferroptotic macrophages increased the expression of IL-1β, IL-6, and IL-23 in microglia. Mechanistically, due to the activation of the NF-κB signaling pathway, the expression of IL-1β and IL-6 was increased. In addition, we established that increased levels of oxidative phosphorylation cause mitochondrial reactive oxygen species generation and unfolded protein response activation and trigger an inflammatory response marked by an increase in IL-23 production. Our findings identified that targeting ferroptosis and IL-23 could be an effective strategy for promoting neurological recovery after SCI.