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; Liefferinge, Joeri Van; Bentea, Eduard; Verbruggen, Lise; Demuyser, Thomas; Deneyer, Lauren; Lewerenz, Jan; Loo, Geert; Keyser, Jacques De; Sato, Hiroki; Maher, Pamela; Methner, Axel; Massie, Ann

doi:10.1186/s12974-016-0787-0

Cited by 25 publications

(20 citation statements)

References 93 publications

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“…Our discovery that xCT is expendable for T cell proliferation and function in vivo unexpectedly yielded results that clearly conflicted with those obtained ex vivo. Although others have reported that either systemic or immune cell-specific disruption of xCT can alleviate T cell-driven EAE (24, 25), we have found that systemic or T cell-specific knockout of xCT does not disrupt the antitumor T cell response. While we focused on T cell proliferation and the adaptive immune response against tumors, it has also been reported that xCT-deficient mice exhibit enhanced expression of IL-1β and TNF-α at the site of 3-methylcholanthrene injection, which was attributed to increased death of macrophages and neutrophils (34).…”

Section: Discussioncontrasting

confidence: 92%

“…If this model is correct, then systemic inhibition of xCT may negatively impact T cell function. Although xCT has been implicated in promoting the pathophysiology of experimental autoimmune encephalomyelitis (EAE), a T cell-driven form of autoimmunity (24, 25), the requirement for xCT in supporting T cell proliferation or antitumor immunity has not been evaluated in vivo.…”

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confidence: 99%

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Cystine–glutamate antiporter xCT deficiency suppresses tumor growth while preserving antitumor immunity

Arensman

Yang

Leahy

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

123

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T cell-invigorating cancer immunotherapies have near-curative potential. However, their clinical benefit is currently limited, as only a fraction of patients respond, suggesting that these regimens may benefit from combination with tumor-targeting treatments. As oncogenic progression is accompanied by alterations in metabolic pathways, tumors often become heavily reliant on antioxidant machinery and may be susceptible to increases in oxidative stress. The cystine–glutamate antiporter xCT is frequently overexpressed in cancer and fuels the production of the antioxidant glutathione; thus, tumors prone to redox stress may be selectively vulnerable to xCT disruption. However, systemic inhibition of xCT may compromise antitumor immunity, as xCT is implicated in supporting antigen-induced T cell proliferation. Therefore, we utilized immune-competent murine tumor models to investigate whether cancer cell expression of xCT was required for tumor growth in vivo and if deletion of host xCT impacted antitumor immune responses. Deletion of xCT in tumor cells led to defective cystine uptake, accumulation of reactive oxygen species, and impaired tumor growth, supporting a cancer cell-autonomous role for xCT. In contrast, we observed that, although T cell proliferation in culture was exquisitely dependent on xCT expression, xCT was dispensable for T cell proliferation in vivo and for the generation of primary and memory immune responses to tumors. These findings prompted the combination of tumor cell xCT deletion with the immunotherapeutic agent anti–CTLA-4, which dramatically increased the frequency and durability of antitumor responses. Together, these results identify a metabolic vulnerability specific to tumors and demonstrate that xCT disruption can expand the efficacy of anticancer immunotherapies.

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Section: Discussioncontrasting

confidence: 92%

mentioning

confidence: 99%

Cystine–glutamate antiporter xCT deficiency suppresses tumor growth while preserving antitumor immunity

Arensman

Yang

Leahy

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

123

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“…Mice lacking xCT, the major component of system x c − are viable [32] and are even protected against 6-hydroxydopamine-induced toxicity [33] probably by a significant decrease in striatal extracellular glutamate levels [34]. The specific cell type that upregulates xCT also seems to be important; while a complete knockout of xCT had no effect on the severity of experimental autoimmune encephalomyelitis, cell-type specific knockout only in immune cells alleviated disease severity [35].…”

Section: Relevance Of Oxytosis In Vivomentioning

confidence: 99%

The role of Ca2+ in cell death caused by oxidative glutamate toxicity and ferroptosis

et al. 2018

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Ca ions play a fundamental role in cell death mediated by oxidative glutamate toxicity or oxytosis, a form of programmed cell death similar and possibly identical to other forms of cell death like ferroptosis. Ca influx from the extracellular space occurs late in a cascade characterized by depletion of the intracellular antioxidant glutathione, increases in cytosolic reactive oxygen species and mitochondrial dysfunction. Here, we aim to compare oxidative glutamate toxicity with ferroptosis, address the signaling pathways that culminate in Ca influx and cell death and discuss the proteins that mediate this. Recent evidence hints toward a role of the machinery responsible for store-operated Ca entry (SOCE), which refills the endoplasmic reticulum (ER) after receptor-mediated ER Ca release or other forms of store depletion. Pharmacological inhibition of SOCE or transcriptional downregulation of proteins involved in SOCE like the ER Ca sensor STIM1, the plasma membrane Ca channels Orai1 and TRPC1 and the linking protein Homer protects against oxidative glutamate toxicity and direct oxidative stress caused by hydrogen peroxide or 1-methyl-4-phenylpyridinium (MPP+) injury, a cellular model of Parkinson's disease. This suggests that SOCE inhibition might have some potential therapeutic effects in human disease associated with oxidative stress like neurodegenerative disorders.

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“…In 2011, Pampliega and colleagues reported that the light chain of the heterodimeric xc- transmembrane protein (known as xCT) responsible for its transporter activity is upregulated in the spinal cord of mice and rats with experimental autoimmune encephalomyelitis (EAE), the most widely characterized rodent model of MS, as well as human MS postmortem tissue [ 6 ]. A recent study by Merckx and colleagues suggests that it is the peripheral immune cells expressing xc-, known to infiltrate the CNS in MS, rather than the resident immune cells that directly contribute to glutamate release and excitotoxicity [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

[18F]FSPG-PET reveals increased cystine/glutamate antiporter (xc-) activity in a mouse model of multiple sclerosis

Hoehne

James

Alam

et al. 2018

J Neuroinflammation

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BackgroundThe cystine/glutamate antiporter (xc-) has been implicated in several neurological disorders and, specifically, in multiple sclerosis (MS) as a mediator of glutamate excitotoxicity and proinflammatory immune responses. We aimed to evaluate an xc-specific positron emission tomography (PET) radiotracer, (4S)-4-(3-[18F]fluoropropyl)-l-glutamate ([18F]FSPG), for its ability to allow non-invasive monitoring of xc- activity in a mouse model of MS.MethodsExperimental autoimmune encephalomyelitis (EAE) was induced in C57BL/6 mice by subcutaneous injection of myelin oligodendrocyte glycoprotein (MOG35–55) peptide in complete Freund’s adjuvant (CFA) followed by pertussis toxin. Control mice received CFA emulsion and pertussis toxin without MOG peptide, while a separate cohort of naïve mice received no treatment. PET studies were performed to investigate the kinetics and distribution of [18F]FSPG in naïve, control, pre-symptomatic, and symptomatic EAE mice, compared to 18F-fluorodeoxyglucose ([18F]FDG). After final PET scans, each mouse was perfused and radioactivity in dissected tissues was measured using a gamma counter. Central nervous system (CNS) tissues were further analyzed using ex vivo autoradiography or western blot. [18F]FSPG uptake in human monocytes, and T cells pre- and post-activation was investigated in vitro.Results[18F]FSPG was found to be more sensitive than [18F]FDG at detecting pathological changes in the spinal cord and brain of EAE mice. Even before clinical signs of disease, a small but significant increase in [18F]FSPG signal was observed in the spinal cord of EAE mice compared to controls. This increase in PET signal became more pronounced in symptomatic EAE mice and was confirmed by ex vivo biodistribution and autoradiography. Likewise, in the brain of symptomatic EAE mice, [18F]FSPG uptake was significantly higher than controls, with the largest changes observed in the cerebellum. Western blot analyses of CNS tissues revealed a significant correlation between light chain of xc- (xCT) protein levels, the subunit of xc- credited with its transporter activity, and [18F]FSPG-PET signal. In vitro [18F]FSPG uptake studies suggest that both activated monocytes and T cells contribute to the observed in vivo PET signal.ConclusionThese data highlight the promise of [18F]FSPG-PET as a technique to provide insights into neuroimmune interactions in MS and the in vivo role of xc- in the development and progression of this disease, thus warranting further investigation.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1080-1) contains supplementary material, which is available to authorized users.

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

Cited by 25 publications

References 93 publications

Cystine–glutamate antiporter xCT deficiency suppresses tumor growth while preserving antitumor immunity

Cystine–glutamate antiporter xCT deficiency suppresses tumor growth while preserving antitumor immunity

The role of Ca2+ in cell death caused by oxidative glutamate toxicity and ferroptosis

[18F]FSPG-PET reveals increased cystine/glutamate antiporter (xc-) activity in a mouse model of multiple sclerosis

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