Advanced search
1 file | 4.74 MB

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

Author
Organization
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.
Keywords
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

Downloads

  • 2785 17Merckx.pdf
    • full text
    • |
    • open access
    • |
    • PDF
    • |
    • 4.74 MB

Citation

Please use this url to cite or link to this publication:

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.
@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},
}

Altmetric
View in Altmetric
Web of Science
Times cited: