Cystine\u2013glutamate antiporter deletion accelerates motor recovery and improves histological outcomes following spinal cord injury in mice

Lindsay Sprimont,Charles Nicaise,Ilse Rooman,Kathleen De Swert,Ann Massie,Pauline Janssen,Mathias Van Bulck,Jacques Gilloteaux

doi:10.1038/s41598-021-91698-y

Lindsay Sprimont, Charles Nicaise + Show 6 more

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https://doi.org/10.1038/s41598-021-91698-y

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Journal: Scientific Reports	Publication Date: Jun 9, 2021
Citations: 10	License type: open-access

Affiliation: University of Namur, Vrije Universiteit Brussel

Abstract

xCT is the specific subunit of System xc-, an antiporter importing cystine while releasing glutamate. Although xCT expression has been found in the spinal cord, its expression and role after spinal cord injury (SCI) remain unknown. The aim of this study was to characterize the role of xCT on functional and histological outcomes following SCI induced in wild-type (xCT+/+) and in xCT-deficient mice (xCT−/−). In the normal mouse spinal cord, slc7a11/xCT mRNA was detected in meningeal fibroblasts, vascular mural cells, astrocytes, motor neurons and to a lesser extent in microglia. slc7a11/xCT gene and protein were upregulated within two weeks post-SCI. xCT−/− mice recovered muscular grip strength as well as pre-SCI weight faster than xCT+/+ mice. Histology of xCT−/− spinal cords revealed significantly more spared motor neurons and a higher number of quiescent microglia. In xCT−/− mice, inflammatory polarization shifted towards higher mRNA expression of ym1 and igf1 (anti-inflammatory) while lower levels of nox2 and tnf-a (pro-inflammatory). Although astrocyte polarization did not differ, we quantified an increased expression of lcn2 mRNA. Our results show that slc7a11/xCT is overexpressed early following SCI and is detrimental to motor neuron survival. xCT deletion modulates intraspinal glial activation by shifting towards an anti-inflammatory profile.

Highlights

XCT is the specific subunit of System xc, an antiporter importing cystine while releasing glutamate
As we previously found an expression of xCT in spinal astrocytes, we wondered how its deficiency would impact on their reactivity following spinal cord injury (SCI)
Significant changes in cell number or shape were observed at two weeks post-SCI in the injured xCT−/− spinal cords, with an increased number of A microglia/macrophages in the lesion epicenter and in regions caudal to the epicenter (Mann–Whitney test, p = 0.028, p = 0.028 and p = 0.028 at epicenter, 500 μm and 1000 μm respectively), together with a decreased number of type B microglia 500 μm away of the epicenter (Mann–Whitney test, p = 0.029) (Fig. 5f)

Summary

Introduction

XCT is the specific subunit of System xc-, an antiporter importing cystine while releasing glutamate. In the normal mouse spinal cord, slc7a11/xCT mRNA was detected in meningeal fibroblasts, vascular mural cells, astrocytes, motor neurons and to a lesser extent in microglia. Minutes to days following spinal cord injury (SCI), hemorrhage, ion dysregulation, production of reactive oxygen species and excitotoxicity are amongst the pathological events responsible for the propagation of damage to spared spinal tissue surrounding the epicenter. During this so-called secondary injury, the volume of the initial trauma expands and leads to additional tissue loss, and worsens the functional deficits[1]. Glutamate is maintained at very low levels in the synaptic cleft and in the extrasynaptic spaces, through a variety of membranous transporters on neuronal or non-neuronal cells

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