Absence of system x on immune cells invading the central nervous system alleviates experimental autoimmune encephalitis.

BACKGROUND

Multiple sclerosis (MS) is an autoimmune demyelinating disease that affects the central nervous system (CNS), leading to neurodegeneration and chronic disability. Accumulating evidence points to a key role for neuroinflammation, oxidative stress, and excitotoxicity in this degenerative process. System x or the cystine/glutamate antiporter could tie these pathological mechanisms together: its activity is enhanced by reactive oxygen species and inflammatory stimuli, and its enhancement might lead to the release of toxic amounts of glutamate, thereby triggering excitotoxicity and neurodegeneration.

METHODS

Semi-quantitative Western blotting served to study protein expression of xCT, the specific subunit of system x, as well as of regulators of xCT transcription, in the normal appearing white matter (NAWM) of MS patients and in the CNS and spleen of mice exposed to experimental autoimmune encephalomyelitis (EAE), an accepted mouse model of MS. We next compared the clinical course of the EAE disease, the extent of demyelination, the infiltration of immune cells and microglial activation in xCT-knockout (xCT) mice and irradiated mice reconstituted in xCT bone marrow (BM), to their proper wild type (xCT) controls.

RESULTS

xCT protein expression levels were upregulated in the NAWM of MS patients and in the brain, spinal cord, and spleen of EAE mice. The pathways involved in this upregulation in NAWM of MS patients remain unresolved. Compared to xCT mice, xCT mice were equally susceptible to EAE, whereas mice transplanted with xCT BM, and as such only exhibiting loss of xCT in their immune cells, were less susceptible to EAE. In none of the above-described conditions, demyelination, microglial activation, or infiltration of immune cells were affected.

CONCLUSIONS

Our findings demonstrate enhancement of xCT protein expression in MS pathology and suggest that system x on immune cells invading the CNS participates to EAE. Since a total loss of system x had no net beneficial effects, these results have important implications for targeting system x for treatment of MS.