Sex differences in peripheral and local immune responses following spinal cord injury

Biological sex has been shown to influence immune function and inflammatory responses. However, most preclinical studies in spinal cord injury (SCI) have predominantly used female animals, potentially introducing a sex bias in our understanding of post-injury inflammation. Given the central role of inflammation in secondary pathology and repair after SCI, males and females are likely to respond differently to this condition, with sex-dependent immune differences potentially shaping injury outcomes. In this study, we explored how biological sex shapes the course of inflammation after SCI and its potential impact on functional recovery.

Locomotor recovery in the SCI mouse model was assessed using the Basso Mouse Scale (BMS). Autonomic recovery was analyzed through the spontaneous void spot assay. Peripheral and local immune responses were characterized by flow cytometry of blood and spinal cord samples, respectively, to track the temporal dynamics of distinct immune cell populations across acute and chronic stages of injury.

We found that, acutely after SCI, males exhibit higher frequencies of circulating myeloid cells, whereas females show higher numbers of these cells in the spinal cord, suggesting delayed myeloid infiltration in males. At this timepoint, females initiate an early attempt to direct some cells toward a phenotype more favorable for tissue repair, with their infiltrative monocytes expressing both pro-inflammatory and alternative activation markers. Sex differences in blood CD54 expression at 4 weeks post-injury suggest that sex-specific immune responses may continue to develop at later stages after SCI. Post-injury welfare outcomes differ between sexes, with males exhibiting delayed post-operative recovery. However, spontaneous long-term functional recovery is largely comparable between sexes after SCI.

Overall, our data identify biological sex as a key determinant of immune and neuroinflammatory responses after SCI while suggesting a limited impact on long-term recovery. These findings highlight the lack of rationale for the underrepresentation of males in preclinical studies and emphasize the importance of sex-inclusive research to better inform personalized therapeutic strategies.