Mature neutrophils promote long-term functional recovery after spinal cord injury in a sex-dependent manner

Abstract

Neutrophils are abundant and complex innate immune cells that act as first responders to tissue injury, with critical roles in combating infection and initiating would healing. Following spinal cord injury (SCI), neutrophils are the first peripheral immune cells to infiltrate the injured spinal cord in large numbers. Despite the growing body of evidence demonstrating sex differences in neutrophil function, sex as a biological variable in neutrophil responses following SCI has yet to be thoroughly investigated. Here we provide novel evidence that neutrophil responses differ by sex following SCI with divergent effects on long-term outcomes. We show substantial sex-dependent shifts in the phenotype of circulating and intraspinal neutrophils across time following SCI. Depletion of neutrophils immediately after SCI reveals a previously unidentified role for mature neutrophils in promoting long-term functional recovery in a sex-dependent manner. Mechanistically, mature neutrophils acquire an inflammation-resolving phenotype in the acutely injured spinal cord and depletion of mature neutrophils exacerbates long-term macrophage accumulation following SCI in a sex-dependent manner. Collectively, our findings provide the first account of marked sex differences in the response of neutrophils to SCI and elucidate a novel and sex-dependent role for mature neutrophils in promoting resolution of inflammation and long-term recovery following SCI.