Increased expression of cystine/glutamate antiporter in multiple sclerosis


Autoria(s): Pampliega Ormaetxea, Olatz; Domercq García, María; Soria Lannes, Federico Nicolás; Villoslada, Pablo; Rodríguez-Antigüedad, Alfredo; Matute Almau, Carlos José
Data(s)

28/03/2012

28/03/2012

03/06/2011

Resumo

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.

Identificador

Journal of Neuroinflammation 8(63) : (2011)

1742-2094

http://hdl.handle.net/10810/7277

10.1186/1742-2094-8-63

Idioma(s)

eng

Publicador

BioMed Central

Relação

http://www.jneuroinflammation.com/content/8/1/63

Direitos

© 2011 Pampliega et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

info:eu-repo/semantics/openAccess

Palavras-Chave #mouse peritoneal-macrophages #system x(c)(-) #bacterial lipopolysaccharide #cerebrospinal fluid #optic nerve #glutamate #oligodendrocytes #neurotoxicity #lesions #excitotoxicity
Tipo

info:eu-repo/semantics/article