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Absence of system xc(-) on immune cells invading the central nervous system alleviates experimental autoimmune encephalitis. / Merckx, Ellen; Albertini, Giulia; Paterka, Magdalena; Jensen, Cathy; Albrecht, Philipp; Dietrich, Michael; Van Liefferinge, Joeri; Bentea, Eduard; Verbruggen, Lise; Demuyser, Thomas; Deneyer, Lauren; Lewerenz, Jan; van Loo, Geert; De Keyser, Jacques; SATO, Hideyo; Maher, Pamela; Methner, Axel; Massie, Ann.

In: Journal of Neuroinflammation, Vol. 14, No. 1, 9, 13.01.2017, p. 1-16.

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Merckx, Ellen ; Albertini, Giulia ; Paterka, Magdalena ; Jensen, Cathy ; Albrecht, Philipp ; Dietrich, Michael ; Van Liefferinge, Joeri ; Bentea, Eduard ; Verbruggen, Lise ; Demuyser, Thomas ; Deneyer, Lauren ; Lewerenz, Jan ; van Loo, Geert ; De Keyser, Jacques ; SATO, Hideyo ; Maher, Pamela ; Methner, Axel ; Massie, Ann. / Absence of system xc(-) on immune cells invading the central nervous system alleviates experimental autoimmune encephalitis. In: Journal of Neuroinflammation. 2017 ; Vol. 14, No. 1. pp. 1-16.

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@article{ec6e8d6bc70b4d85842d7448d257e82d,
title = "Absence of system xc(-) on immune cells invading the central nervous system alleviates experimental autoimmune encephalitis",
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 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.METHODS: 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.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 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.",
keywords = "Experimental autoimmune encephalomyelitis, Glutamate, Multiple sclerosis, System x, XCT",
author = "Ellen Merckx and Giulia Albertini and Magdalena Paterka and Cathy Jensen and Philipp Albrecht and Michael Dietrich and {Van Liefferinge}, Joeri and Eduard Bentea and Lise Verbruggen and Thomas Demuyser and Lauren Deneyer and Jan Lewerenz and {van Loo}, Geert and {De Keyser}, Jacques and Hideyo SATO and Pamela Maher and Axel Methner and Ann Massie",
year = "2017",
month = "1",
day = "13",
doi = "10.1186/s12974-016-0787-0",
language = "English",
volume = "14",
pages = "1--16",
journal = "Journal of Neuroinflammation",
issn = "1742-2094",
publisher = "BioMed Central",
number = "1",

}

RIS

TY - JOUR

T1 - Absence of system xc(-) on immune cells invading the central nervous system alleviates experimental autoimmune encephalitis

AU - Merckx, Ellen

AU - Albertini, Giulia

AU - Paterka, Magdalena

AU - Jensen, Cathy

AU - Albrecht, Philipp

AU - Dietrich, Michael

AU - Van Liefferinge, Joeri

AU - Bentea, Eduard

AU - Verbruggen, Lise

AU - Demuyser, Thomas

AU - Deneyer, Lauren

AU - Lewerenz, Jan

AU - van Loo, Geert

AU - De Keyser, Jacques

AU - SATO, Hideyo

AU - Maher, Pamela

AU - Methner, Axel

AU - Massie, Ann

PY - 2017/1/13

Y1 - 2017/1/13

N2 - 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 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.METHODS: 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.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 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.

AB - 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 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.METHODS: 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.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 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.

KW - Experimental autoimmune encephalomyelitis

KW - Glutamate

KW - Multiple sclerosis

KW - System x

KW - XCT

UR - http://www.scopus.com/inward/record.url?scp=85009424150&partnerID=8YFLogxK

U2 - 10.1186/s12974-016-0787-0

DO - 10.1186/s12974-016-0787-0

M3 - Article

C2 - 28086920

VL - 14

SP - 1

EP - 16

JO - Journal of Neuroinflammation

JF - Journal of Neuroinflammation

SN - 1742-2094

IS - 1

M1 - 9

ER -

ID: 28609308