title: Increased expression of cystine/glutamate antiporter in multiple sclerosis.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Neurotek-UPV/EHU, Parque Tecnológico de Bizkaia, Zamudio, Bizkaia, Spain.
authors.forename: Olatz
authors.initials: O
authors.lastname: Pampliega
authors.forename: María
authors.initials: M
authors.lastname: Domercq
authors.forename: Federico N
authors.initials: FN
authors.lastname: Soria
authors.forename: Pablo
authors.initials: P
authors.lastname: Villoslada
authors.forename: Alfredo
authors.initials: A
authors.lastname: Rodríguez-Antigüedad
authors.forename: Carlos
authors.initials: C
authors.lastname: Matute
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D027182:Amino Acid Transport System y+ / Q000235:genetics / Q000378:metabolism*; D026922:Amino Acid Transport Systems, Acidic; D000818:Animals; D002460:Cell Line; D003553:Cystine / Q000378:metabolism*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D009900:Optic Nerve / Q000473:pathology; D051381:Rats; D011917:Rats, Inbred Lew; D013116:Spinal Cord / Q000473:pathology; D055815:Young Adult
chemical_list: D027182:Amino Acid Transport System y+; D026922:Amino Acid Transport Systems, Acidic; D003553:Cystine; D018698:Glutamic Acid; D005978:Glutathione; C118895:SLC7A11 protein, human; C000723960:Slc7a11 protein, rat