Mature neutrophils promote long-term functional recovery after spinal cord injury in a sex-dependent manner
Following spinal cord injury (SCI), neutrophils are the first peripheral immune cells to infiltrate the injured spinal cord in large numbers. There is a growing body of evidence demonstrating sex differences in neutrophil function, however, the role of sex as a biological variable in neutrophil response following SCI remain unclear. Additionally, while divergent roles for mature and immature neutrophil subsets have been observed, subset-specific contributions of neutrophils to functional recovery following SCI have not been fully characterized. Here, we provide novel evidence that systemic and localized neutrophil responses differ by sex following SCI. Antibody- mediated depletion of neutrophils following SCI revealed a previously unidentified role for mature neutrophils in promoting long-term functional recovery in a sex-dependent manner. We performed single-cell RNA sequencing analysis using publicly available datasets and discovered dramatic shifts in the phenotype of intraspinal neutrophils across time following SCI. We identified that mature neutrophils in the acutely injured spinal cord upregulate genes associated with resolution of inflammation. Furthermore, we found that depletion of mature neutrophils exacerbates long-term macrophage accumulation following SCI in a sex-dependent manner. Finally, we show that the beneficial properties of neutrophils in the injured spinal cord are temporally specific. Collectively, these data provide a first account of sex differences in the response of neutrophils to SCI. Our findings elucidate a novel and sex-dependent role for mature neutrophils in promoting resolution of inflammation and long-term recovery following SCI.