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

This is the authors' abstract. We don't add key points for this paper.

Schematic diagram of the specific mechanism by which ferroptotic macrophages aggravate SCI. After SCI, ferroptotic macrophages upregulate the production of IL-1β and IL-6 in neighboring microglia by activating the NF-κB signaling pathway. In addition, elevated mtROS levels in microglia triggered the PERK pathway in the UPR, which in turn increased the expression of IL-23. The addition of Fer-1 and antibodies against IL-23p19 may reduce microglia-derived IL-1β, IL-6, and IL-23 secretion, protect neurons from inflammatory factor damage, and inhibit the differentiation of pathogenic Th17 cells following SCI. • Macrophages might be the predominant cell type undergoing ferroptosis following SCI. • Microglia surrounded ferroptotic macrophages after SCI. • FeMs aggravate SCI by inducing the proinflammatory properties of microglia. 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.