Abstract
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.
Footnotes
The authors declare no competing financial interests.
This work was funded by the Department of Defense SCIRP W81XWH-12-1-0563, The Craig H. Neilsen Foundation, The Dana Foundation, The Oxnard Foundation of California, The Roman Reed Fund from the State of California, the National Institutes of Health, NINDS R01NSC39278, NINDS F32NS096883, and the UCSF Sandler Foundation in Basic Science Integrative Research Award.
D.A.M. and S.L.Co-first authors
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
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