Increased expression of cystine/glutamate antiporter in multiple sclerosis
Journal of Neuroinflammation. 2011-01-01; 8(1): 63
DOI: 10.1186/1742-2094-8-63
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Pampliega O(1), Domercq M, Soria FN, Villoslada P, Rodríguez-Antigüedad A, Matute C.
Author information:
(1)Neurotek-UPV/EHU, Parque Tecnológico de Bizkaia, Zamudio, Bizkaia, Spain.
BACKGROUND: Glutamate excitotoxicity contributes to oligodendrocyte and tissue
damage in multiple sclerosis (MS). Intriguingly, glutamate level in plasma and
cerebrospinal fluid of MS patients is elevated, a feature which may be related to
the pathophysiology of this disease. In addition to glutamate transporters,
levels of extracellular glutamate are controlled by cystine/glutamate antiporter
x(c)⁻, an exchanger that provides intracellular cystine for production of
glutathione, the major cellular antioxidant. The objective of this study was to
analyze the role of the system x(c)⁻ in glutamate homeostasis alterations in MS
pathology.
METHODS: Primary cultures of human monocytes and the cell line U-937 were used to
investigate the mechanism of glutamate release. Expression of cystine glutamate
exchanger (xCT) was quantified by quantitative PCR, Western blot, flow cytometry
and immunohistochemistry in monocytes in vitro, in animals with experimental
autoimmune encephalomyelitis (EAE), the animal model of MS, and in samples of MS
patients.
RESULTS AND DISCUSSION: We show here that human activated monocytes release
glutamate through cystine/glutamate antiporter x(c)⁻ and that the expression of
the catalytic subunit xCT is upregulated as a consequence of monocyte activation.
In addition, xCT expression is also increased in EAE and in the disease proper.
In the later, high expression of xCT occurs both in the central nervous system
(CNS) and in peripheral blood cells. In particular, cells from
monocyte-macrophage-microglia lineage have higher xCT expression in MS and in
EAE, indicating that immune activation upregulates xCT levels, which may result
in higher glutamate release and contribution to excitotoxic damage to
oligodendrocytes.
CONCLUSIONS: Together, these results reveal that increased expression of the
cystine/glutamate antiporter system x(c)⁻ in MS provides a link between
inflammation and excitotoxicity in demyelinating diseases.
DOI: 10.1186/1742-2094-8-63
PMCID: PMC3117706
PMID: 21639880 [Indexed for MEDLINE]