The heme-binding protein hemopexin promotes functional recovery and tissue protection after spinal cord injury via sex-specific regulation of inflammation and ferroptosis

In individuals with spinal cord injury (SCI), intraparenchymal hemorrhage is correlated with worsened functional recovery. Hemorrhage is a well described contributor to secondary tissue damage, which expands the tissue damage beyond the initial injury. Hence, targeting hemorrhage mediated secondary damage is critical for tissue preservation and neurological outcome. In this work, we investigate the role of hemopexin (Hx), an acute-phase plasma glycoprotein that sequesters the blood breakdown product heme, thus preventing toxicity and inflammation induced by intraparenchymal hemorrhage after SCI.In a mouse model of lower thoracic (T10/T11) spinal cord contusion injury, Hx and its receptor low-density lipoprotein receptor-related protein 1 (LRP-1), were significantly upregulated after SCI. Hx was detected predominantly in astrocytes, while LRP-1 was primarily colocalized with macrophages. The absence of Hx worsened locomotor recovery in male and female Hx^-/- mice and reduced neuronal survival after SCI. Sex specific differences were observed in neutrophil numbers, neuronal survival and levels of lipid peroxidation, suggesting differential mechanisms of heme mediated tissue damage. These results support the detrimental role of intraparenchymal hemorrhage after SCI and pressing need to mitigate hemoglobin mediated tissue toxicity.