Abstract
BackgroundGlutamate 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 xc-, 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 xc- in glutamate homeostasis alterations in MS pathology.MethodsPrimary 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 discussionWe show here that human activated monocytes release glutamate through cystine/glutamate antiporter xc- 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.ConclusionsTogether, these results reveal that increased expression of the cystine/glutamate antiporter system xc- in MS provides a link between inflammation and excitotoxicity in demyelinating diseases.
Highlights
Glutamate excitotoxicity contributes to oligodendrocyte and tissue damage in multiple sclerosis (MS)
Human monocytes release glutamate through cystine/ glutamate antiporter We have previously demonstrated that activation of U-937 monocytes induces glutamate release [13]
We analyzed the mechanism of glutamate release in U-937 cells as well as in peripheral blood monocytes in vitro
Summary
Glutamate excitotoxicity contributes to oligodendrocyte and tissue damage in multiple sclerosis (MS). Glutamate level in plasma and cerebrospinal fluid of MS patients is elevated, a feature which may be related to the pathophysiology of this disease. Multiple sclerosis (MS) is a chronic, degenerative disease of the CNS, which is characterized by focal lesions with inflammation, demyelination, infiltration of immune cells, oligodendroglial death and axonal degeneration [1,2,3]. Glutamate is increased in cerebrospinal fluid (CSF) from MS patients with acute lesions, whereas in silent ones glutamate is similar to controls [11]. Glutamate plasma levels are increased in relapsing MS patients [13]. Together, these data point to an implication of glutamate excitotoxicity in MS pathology [14,15]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
