The cystine‐glutamate exchanger (xCT, Slc7a11) is expressed in significant concentrations in a subpopulation of astrocytes in the mouse brain

Ottestad-Hansen, Sigrid; Hu, Qiu Xiang; Follin-Arbelet, Virgine Veronique; Bentea, Eduard; Sato, Hiroki; Massie, Ann; Zhou, Yun; Danbolt, Niels Christian

doi:10.1002/glia.23294

Cited by 70 publications

(55 citation statements)

References 83 publications

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“…Notably, a subpopulation of astrocytes are labeled with an xCT antibody, but with greatly varying intensities [39]. However, deficiency of xCT in mice is associated with no apparent problems under standard breeding conditions [37,38].…”

Section: Gsh-dependent Protection Of Brain Cellsmentioning

confidence: 99%

Circadian control of BDNF-mediated Nrf2 activation in astrocytes protects dopaminergic neurons from ferroptosis

Ishii

Warabi

Mann

2019

Free Radical Biology and Medicine

144

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Astrocyte-neuron interactions protect neurons from iron-mediated toxicity. As dopamine can be metabolized to reactive quinones, dopaminergic neurons are susceptible to oxidative damage and ferroptosis-like induced cell death. Detoxification enzymes are required to protect neurons. Brain-derived neurotrophic factor (BDNF) plays a key role in the regulation of redox sensitive transcription factor Nrf2 in astrocytes and metabolic cooperation between astrocytes and neurons. This article reviews the importance of BDNF and astrocyte-neuron interactions in the protection of neurons against oxidative damages in rodent brains. We previously proposed that BDNF activates Nrf2 via the truncated TrkB.T1 and p75 receptor complex in astrocytes. Stimulation by BDNF generates the signaling molecule ceramide, which activates PKCζ leading to induction of the CK2-Nrf2 signaling axis. As a cell clock regulates p75 expression, we suggested that BDNF effectively activates Nrf2 in astrocytes during the rest phase. In contrast, neurons express both TrkB.FL and TrkB.T1, and TrkB.FL tyrosine kinase activity inhibits p75-dependent ceramide generation and internalizes p75. Therefore, BDNF may not effectively activate Nrf2 in neurons. Notably, neurons only weakly activate detoxification and antioxidant enzymes/proteins via the Nrf2-ARE signaling axis. Thus, astrocytes may provide relevant transcripts and/or proteins to neurons via microparticles/exosomes increasing neuronal resistance to oxidative stress. Circadian increases in the levels of circulating glucocorticoids may further facilitate material transfer from astrocytes to neurons via the stimulation of pannexin 1 channels-P2X7R signaling pathway in astrocytes at the beginning of the active phase. Dysregulation of astrocyte-neuron interactions could therefore contribute to the pathogenesis of neurodegenerative diseases including Parkinson's disease.

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Section: Gsh-dependent Protection Of Brain Cellsmentioning

confidence: 99%

Circadian control of BDNF-mediated Nrf2 activation in astrocytes protects dopaminergic neurons from ferroptosis

Ishii

Warabi

Mann

2019

Free Radical Biology and Medicine

144

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“…1,2 Although xCT expression is inducible in a number of tissues, its constitutive expression is limited to the central nervous system (CNS) and lymphoid organs, including the thymus and spleen. 5,6 Sx c − imports cystine (CySS) and exports glutamate (Glu) with 1:1 stoichiometry across the cellular plasma membrane. 5,6 Sx c − imports cystine (CySS) and exports glutamate (Glu) with 1:1 stoichiometry across the cellular plasma membrane.…”

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confidence: 99%

“…3,4 Within the CNS, xCT is detected in most major brain regions, with studies investigating its cellular source demonstrating that it is predominantly of astrocytic origin. 5,6 Sx c − imports cystine (CySS) and exports glutamate (Glu) with 1:1 stoichiometry across the cellular plasma membrane. 7 Early functional characterization of Sx c − established its fundamental physiologic role as a cellular CySS supplier.…”

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confidence: 99%

Decreased epileptogenesis in mice lacking the System x_c⁻ transporter occurs in association with a reduction in AMPA receptor subunit GluA1

Sears

Hewett

2019

Epilepsia Open

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Summary Objective Although the cystine/glutamate antiporter System xc− (Sxc−) plays a permissive role in glioma‐associated seizures, its contribution to other acquired epilepsies has not been determined. As such, the present study investigates whether and how Sxc− contributes to the pentylenetetrazole (PTZ) chemical kindling model of epileptogenesis. Methods Male Sxc− null (sut/sut) mice and their wild‐type littermates were administered PTZ (i.p.) daily for up to 21 days (kindling paradigm). Seizure severity was scored on a 5‐point behavioral scale. Mossy fiber sprouting, cellular degeneration, and Sxc− light chain (xCT) messenger RNA (mRNA) were explored using Timm staining, thionin staining, and real‐time quantitative polymerase chain reaction (qPCR), respectively. Levels of reduced and oxidized glutathione and cysteine were determined via high‐performance liquid chromatography (HPLC). Plasma membrane protein levels of glutamate and γ‐aminobutyric acid (GABA) receptor subunits as well as the K+/Cl− co‐transporter KCC2 were quantified via western blot analysis. Results Repeated administration of PTZ produced chemical kindling in only 50% of Sxc− null mice as compared to 82% of wild‐type littermate control mice. Kindling did not result in any changes in xCT mRNA levels assessed in wild‐type mice. No cellular degeneration or mossy fiber sprouting was discernible in either genotype. Except for a small, but significant, decrease in oxidized cysteine in the hippocampus, no other change in measured redox couples was determined in Sxc− null mice. Cortical levels of the α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptor subunit GluA1 were decreased in Sxc− null mice as compared to wild‐type littermates, whereas all other proteins tested showed no difference between genotypes. Significance This study provides the first evidence that Sxc− signaling contributes to epileptogenesis in the PTZ kindling model of acquired epilepsy. Further data indicate that a reduction in AMPA receptor signaling could underlie the resistance to PTZ kindling uncovered in Sxc− null mice.

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“…Recently, Ottestad-Hansen et al (2018) demonstrated that, while astrocytes express xCT, the other cell types of the CNS, such as neurons, oligodendrocytes and microglia, are not positively labeled . System x 2 c transports cystine into the cells where it is reduced to cysteine, important for glutathione (GSH) synthesis.…”

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confidence: 99%

Genetic deletion of xCT attenuates peripheral and central inflammation and mitigates LPS‐induced sickness and depressive‐like behavior in mice

Albertini

Deneyer

Ottestad-Hansen

et al. 2018

Glia

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The communication between the immune and central nervous system (CNS) is affected in many neurological disorders. Peripheral injections of the endotoxin lipopolysaccharide (LPS) are widely used to study this communication: an LPS challenge leads to a biphasic syndrome that starts with acute sickness and is followed by persistent brain inflammation and chronic behavioral alterations such as depressive-like symptoms. In vitro, the response to LPS treatment has been shown to involve enhanced expression of system x c - . This cystine-glutamate antiporter, with xCT as specific subunit, represents the main glial provider of extracellular glutamate in mouse hippocampus. Here we injected male xCT knockout and wildtype mice with a single intraperitoneal dose of 5 mg/kg LPS. LPS-injection increased hippocampal xCT expression but did not alter the mainly astroglial localization of the xCT protein. Peripheral and central inflammation (as defined by cytokine levels and morphological activation of microglia) as well as LPS-induced sickness and depressive-like behavior were significantly attenuated in xCT-deficient mice compared with wildtype mice. Our study is the first to demonstrate the involvement of system x c - in peripheral and central inflammation in vivo and the potential therapeutic relevance of its inhibition in brain disorders characterized by peripheral and central inflammation, such as depression.

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The cystine‐glutamate exchanger (xCT, Slc7a11) is expressed in significant concentrations in a subpopulation of astrocytes in the mouse brain

Abstract: xCT is present in select blood/brain/CSF interface areas and in an astrocyte subpopulation, in sufficient quantities to support the notion that system xc- provides physiologically relevant transport activity.

Cited by 70 publications

References 83 publications

Circadian control of BDNF-mediated Nrf2 activation in astrocytes protects dopaminergic neurons from ferroptosis

Circadian control of BDNF-mediated Nrf2 activation in astrocytes protects dopaminergic neurons from ferroptosis

Decreased epileptogenesis in mice lacking the System x_c⁻ transporter occurs in association with a reduction in AMPA receptor subunit GluA1

Genetic deletion of xCT attenuates peripheral and central inflammation and mitigates LPS‐induced sickness and depressive‐like behavior in mice

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The cystine‐glutamate exchanger (xCT, Slc7a11) is expressed in significant concentrations in a subpopulation of astrocytes in the mouse brain

Abstract: xCT is present in select blood/brain/CSF interface areas and in an astrocyte subpopulation, in sufficient quantities to support the notion that system xc- provides physiologically relevant transport activity.

Cited by 70 publications

References 83 publications

Circadian control of BDNF-mediated Nrf2 activation in astrocytes protects dopaminergic neurons from ferroptosis

Circadian control of BDNF-mediated Nrf2 activation in astrocytes protects dopaminergic neurons from ferroptosis

Decreased epileptogenesis in mice lacking the System xc− transporter occurs in association with a reduction in AMPA receptor subunit GluA1

Genetic deletion of xCT attenuates peripheral and central inflammation and mitigates LPS‐induced sickness and depressive‐like behavior in mice

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Decreased epileptogenesis in mice lacking the System x_c⁻ transporter occurs in association with a reduction in AMPA receptor subunit GluA1