TY - JOUR T1 - Early Targeting of L-Selectin on Leukocytes Promotes Recovery after Spinal Cord Injury, Implicating Novel Mechanisms of Pathogenesis JF - eneuro JO - eNeuro DO - 10.1523/ENEURO.0101-18.2018 SP - ENEURO.0101-18.2018 AU - D. A. McCreedy AU - S. Lee AU - C. J. Sontag AU - P. Weinstein AU - A. D. Olivas AU - A. F. Martinez AU - T. M. Fandel AU - A. Trivedi AU - C. A. Lowell AU - S. D. Rosen AU - L. J. Noble-Haeusslein Y1 - 2018/08/13 UR - http://www.eneuro.org/content/early/2018/08/13/ENEURO.0101-18.2018.abstract N2 - L-selectin, a lectin-like receptor on all leukocyte classes, functions in adhesive and signaling roles in the recruitment of myeloid cells from the blood to sites of inflammation. Herein, we consider L-selectin as a determinant of neurological recovery in a murine model of spinal cord injury. Spinal cord-injured, L-selectin knockout mice (male) showed improved long-term recovery with greater white matter sparing relative to wildtype mice and reduced oxidative stress in the injured cord at 72 hours post-spinal cord injury. There was a partial and transient reduction in accumulation of neutrophils in the injured spinal cords of knockouts at 24 hours post-injury. To complement these findings with knockout mice, we sought a pharmacologic means for lowering L-selectin levels. We found that diclofenac, a nonsteroidal anti-inflammatory drug, induced the shedding of L-selectin from the cell surface of myeloid subsets, specifically neutrophils and non-classical monocytes, in the blood and the injured spinal cord. Diclofenac administration to injured wildtype mice enhanced neurological recovery to a level comparable to that of knockouts but did not improve recovery in knockouts. While diclofenac treatment had no effect on myeloid cell accumulation, there was a reduction in oxidative stress at 72 hours post-spinal cord injury. These findings implicate L-selectin in secondary pathogenesis beyond a role in leukocyte recruitment and raise the possibility of repurposing diclofenac for the treatment of spinal cord injury.Significance Statement In this study, we establish L-selectin, an adhesion and signaling receptor on immune cells, as a determinant of long-term recovery and tissue sparing after spinal cord injury. We demonstrate that L-selectin contributes to secondary pathogenesis during acute inflammation, and implicate L-selectin in novel roles other than recruitment. We also report a strategy to improve recovery by employing diclofenac, an FDA-approved NSAID that induces the shedding of L-selectin from the surface of innate immune cells. Our findings demonstrate a critical time-period for anti-inflammatory intervention in a murine model of spinal cord injury and suggest that diclofenac be tested as an acute therapy for attenuating neurologic deficits following spinal cord injury in humans. ER -