title: Absence of system xc-on immune cells invading the central nervous system alleviates experimental autoimmune encephalitis.
abstract: 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 xc-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.
  
  
  
  Semi-quantitative Western blotting served to study protein expression of xCT, the specific subunit of system xc-, 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.
  
  
  
  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.
  
  
  
  Our findings demonstrate enhancement of xCT protein expression in MS pathology and suggest that system xc-on immune cells invading the CNS participates to EAE. Since a total loss of system xc-had no net beneficial effects, these results have important implications for targeting system xc-for treatment of MS.
authors.affiliation: Center for Neurosciences (C4N), Department of Pharmaceutical Biotechnology and Molecular Biology, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium.
authors.forename: Ellen
authors.initials: E
authors.lastname: Merckx
authors.affiliation: Center for Neurosciences (C4N), Department of Pharmaceutical Chemistry and Drug Analysis, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Giulia
authors.initials: G
authors.lastname: Albertini
authors.affiliation: Department of Neurology, University Medical Center of the Johannes Gutenberg-University of Mainz, Mainz, Germany.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Paterka
authors.affiliation: Center for Neurosciences (C4N), Department of Pharmaceutical Biotechnology and Molecular Biology, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium.
authors.forename: Cathy
authors.initials: C
authors.lastname: Jensen
authors.affiliation: Department of Neurology, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Albrecht
authors.affiliation: Department of Neurology, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Dietrich
authors.affiliation: Center for Neurosciences (C4N), Department of Pharmaceutical Chemistry and Drug Analysis, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Joeri
authors.initials: J
authors.lastname: Van Liefferinge
authors.affiliation: Center for Neurosciences (C4N), Department of Pharmaceutical Biotechnology and Molecular Biology, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium.
authors.forename: Eduard
authors.initials: E
authors.lastname: Bentea
authors.affiliation: Center for Neurosciences (C4N), Department of Pharmaceutical Biotechnology and Molecular Biology, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium.
authors.forename: Lise
authors.initials: L
authors.lastname: Verbruggen
authors.affiliation: Center for Neurosciences (C4N), Department of Pharmaceutical Chemistry and Drug Analysis, Vrije Universiteit Brussel, Brussels, Belgium.
authors.forename: Thomas
authors.initials: T
authors.lastname: Demuyser
authors.affiliation: Center for Neurosciences (C4N), Department of Pharmaceutical Biotechnology and Molecular Biology, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium.
authors.forename: Lauren
authors.initials: L
authors.lastname: Deneyer
authors.affiliation: Department of Neurology, University of Ulm, Ulm, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Lewerenz
authors.affiliation: Inflammation Research Center, VIB and Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Geert
authors.initials: G
authors.lastname: van Loo
authors.affiliation: Center for Neurosciences (C4N), Department of Neurology, Universitair Ziekenhuis Brussel, Brussels, Belgium.
authors.forename: Jacques
authors.initials: J
authors.lastname: De Keyser
authors.affiliation: Department of Medical Technology, Faculty of Medicine, Niigata University, Niigata, Japan.
authors.forename: Hideyo
authors.initials: H
authors.lastname: Sato
authors.affiliation: Cellular Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA.
authors.forename: Pamela
authors.initials: P
authors.lastname: Maher
authors.affiliation: Department of Neurology, University Medical Center of the Johannes Gutenberg-University of Mainz, Mainz, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Methner
authors.affiliation: Center for Neurosciences (C4N), Department of Pharmaceutical Biotechnology and Molecular Biology, Vrije Universiteit Brussel, Laarbeeklaan 103, 1090, Brussels, Belgium. amassie@vub.ac.be.
authors.forename: Ann
authors.initials: A
authors.lastname: Massie
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D027182:Amino Acid Transport System y+ / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D000818:Animals; D002490:Central Nervous System / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D007111:Immunity, Cellular / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017628:Microglia / Q000473:pathology / Q000502:physiology; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
chemical_list: D027182:Amino Acid Transport System y+; C492255:Slc7a11 protein, mouse
keywords: Experimental autoimmune encephalomyelitis; Glutamate; Multiple sclerosis; System xc −; xCT