Elevated xCT expression levels in normal appearing white matter of multiple sclerosis patients: a protective mechanism or a trigger for excitotoxic damage?

Multiple sclerosis (MS) is one of the most frequent disorders of the central nervous system. Excitotoxicity as well as oxidative stress are part of the pathogenesis, in accordance to other neurological diseases. The cystine/glutamate antiporter or system xc-, with xCT as specific subunit, imports cystine in exchange for glutamate and can as such affect intracellular antioxidant as well as extracellular glutamate levels. Oxidative stress induces the expression of xCT and could consequently aggravate excitotoxic damage. We found increased xCT protein expression levels in the normal appearing white matter of MS patients compared to healthy controls, suggesting an involvement of system xc- in the pathogenesis of MS. However, in an animal model for MS, i.e. the TMEV (Theiler's murine encephalomyelitis virus) mouse model, we could not observe any effect on xCT expression in spinal cord. Also in vitro, TMEV infection of macrophages could not affect xCT expression or system xc- activity. We next compared the susceptibility of xCT-/- mice in the EAE (experimental autoimmune encephalomyelitis) model to wildtype littermates. No significant difference could be observed in the appearance of the clinical signs between both genotypes. Current experiments will reveal whether a restricted loss of system xc- (i.e. only in immune cells while brain levels remain unaffected) could protect against EAE-induced symptoms/damage. We hypothesize that the infiltrating immune cells could induce excitotoxic damage in the spinal cord as it has been shown that xCT expression is increased in these cells as well as in the spleen (contrary to brain) after EAE induction.