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Absence of system xc⁻ on immune cells invading the central nervous system alleviates experimental autoimmune encephalitis

Ellen Merckx, Giulia Albertini, Magdalena Paterka, Cathy Jensen, Philipp Albrecht, Michael Dietrich, Joeri Van Liefferinge, Eduard Bentea, Lise Verbruggen, Thomas Demuyser, et al. (2017) JOURNAL OF NEUROINFLAMMATION. 14.
abstract
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(c)- 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(c)-, 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(c)- on immune cells invading the CNS participates to EAE. Since a total loss of system x(c)- had no net beneficial effects, these results have important implications for targeting system x(c)- for treatment of MS.
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author
organization
alternative title
Absence of system x(c)(-) on immune cells invading the central nervous system alleviates experimental autoimmune encephalitis
year
type
journalArticle (original)
publication status
published
subject
keyword
EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS, NITRIC-OXIDE SYNTHASE, METABOTROPIC GLUTAMATE RECEPTORS, PROGRESSIVE MULTIPLE-SCLEROSIS, MOUSE, PERITONEAL-MACROPHAGES, BLOOD-BRAIN-BARRIER, OXIDATIVE STRESS, CYSTINE/GLUTAMATE ANTIPORTER, BACTERIAL LIPOPOLYSACCHARIDE, LYMPHOCYTE-ACTIVATION, System x(c)(-), xCT, Glutamate, Multiple sclerosis, Experimental, autoimmune encephalomyelitis
journal title
JOURNAL OF NEUROINFLAMMATION
J. Neuroinflamm.
volume
14
article number
9
pages
16 pages
Web of Science type
Article
Web of Science id
000391895400001
ISSN
1742-2094
DOI
10.1186/s12974-016-0787-0
language
English
UGent publication?
yes
classification
A1
copyright statement
Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
id
8510042
handle
http://hdl.handle.net/1854/LU-8510042
date created
2017-02-17 15:36:38
date last changed
2017-05-10 14:28:20
@article{8510042,
  abstract     = {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(c)- 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(c)-, 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(c)- on immune cells invading the CNS participates to EAE. Since a total loss of system x(c)- had no net beneficial effects, these results have important implications for targeting system x(c)- for treatment of MS.},
  articleno    = {9},
  author       = {Merckx, Ellen and Albertini, Giulia and Paterka, Magdalena and Jensen, Cathy and Albrecht, Philipp and Dietrich, Michael and Van Liefferinge, Joeri and Bentea, Eduard and Verbruggen, Lise and Demuyser, Thomas and Deneyer, Lauren and Lewerenz, Jan and van Loo, Geert and De Keyser, Jacques and Sato, Hideyo and Maher, Pamela and Methner, Axel and Massie, Ann},
  issn         = {1742-2094},
  journal      = {JOURNAL OF NEUROINFLAMMATION},
  keyword      = {EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS,NITRIC-OXIDE SYNTHASE,METABOTROPIC GLUTAMATE RECEPTORS,PROGRESSIVE MULTIPLE-SCLEROSIS,MOUSE,PERITONEAL-MACROPHAGES,BLOOD-BRAIN-BARRIER,OXIDATIVE STRESS,CYSTINE/GLUTAMATE ANTIPORTER,BACTERIAL LIPOPOLYSACCHARIDE,LYMPHOCYTE-ACTIVATION,System x(c)(-),xCT,Glutamate,Multiple sclerosis,Experimental,autoimmune encephalomyelitis},
  language     = {eng},
  pages        = {16},
  title        = {Absence of system xc\unmatched{207b} on immune cells invading the central nervous system alleviates experimental autoimmune encephalitis},
  url          = {http://dx.doi.org/10.1186/s12974-016-0787-0},
  volume       = {14},
  year         = {2017},
}

Chicago
Merckx, Ellen, Giulia Albertini, Magdalena Paterka, Cathy Jensen, Philipp Albrecht, Michael Dietrich, Joeri Van Liefferinge, et al. 2017. “Absence of System Xc on Immune Cells Invading the Central Nervous System Alleviates Experimental Autoimmune Encephalitis.” Journal of Neuroinflammation 14.
APA
Merckx, Ellen, Albertini, G., Paterka, M., Jensen, C., Albrecht, P., Dietrich, M., Van Liefferinge, J., et al. (2017). Absence of system xc on immune cells invading the central nervous system alleviates experimental autoimmune encephalitis. JOURNAL OF NEUROINFLAMMATION, 14.
Vancouver
1.
Merckx E, Albertini G, Paterka M, Jensen C, Albrecht P, Dietrich M, et al. Absence of system xc on immune cells invading the central nervous system alleviates experimental autoimmune encephalitis. JOURNAL OF NEUROINFLAMMATION. 2017;14.
MLA
Merckx, Ellen, Giulia Albertini, Magdalena Paterka, et al. “Absence of System Xc on Immune Cells Invading the Central Nervous System Alleviates Experimental Autoimmune Encephalitis.” JOURNAL OF NEUROINFLAMMATION 14 (2017): n. pag. Print.