L-selectin shedding regulates functional recovery and neutrophil clearance following spinal cord injury in a sex-dependent manner

During the acute phase of spinal cord injury (SCI), neutrophils infiltrate in large numbers and can exacerbate inflammation, secondary tissue damage, and neurological deficits. L-selectin is a signaling and adhesion receptor that has been shown to facilitate neutrophil recruitment and secondary injury after SCI. During neutrophil activation, L-selectin is typically cleaved or shed from the cell surface and augmenting L-selectin shedding can improve hindlimb recovery and tissue sparing following SCI in male mice. However, it is unclear how endogenous L-selectin shedding regulates neutrophil responses and functional recovery after SCI, particularly when also considering sex as a biological variable. In this study, we investigated the sex-dependent role of endogenous L-selectin shedding in neutrophil function and long-term outcomes in a murine thoracic contusion model of SCI. We found that endogenous L-selectin shedding improves long-term functional recovery and white matter sparing in female, but not male, mice. In addition, we demonstrate that L-selectin shedding alters neutrophil accumulation in a sex-dependent manner. While L-selectin shedding does not mediate neutrophil activation or effector functions, we found that neutrophil clearance is facilitated by L-selectin shedding in female mice alone. These results demonstrate that endogenous L-selectin shedding is a critical and sex-dependent mediator of neutrophil accumulation and clearance, as well as long-term functional outcomes, after SCI.