Interleukin 1β Regulation of the System xc− Substrate-specific Subunit, xCT, in Primary Mouse Astrocytes Involves the RNA-binding Protein HuR

Shi, Jingxue; He, Yan; Hewett, Sandra J.; Hewett, James A.

doi:10.1074/jbc.m115.697821

Cited by 14 publications

(18 citation statements)

References 73 publications

(46 reference statements)

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“…xCT mRNA expression was mainly upregulated in Müller cells, while the expression in isolated PRs remained stable (Fig. 3f), confirming previous reports [34,35].…”

Section: Il-1β Disrupts Glutamate Homeostasis In Müller Glial Cellssupporting

confidence: 90%

IL-1β induces rod degeneration through the disruption of retinal glutamate homeostasis

Charles-Messance

Blot

Couturier

et al. 2020

J Neuroinflammation

154

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Background: Age-related macular degeneration is characterized by the accumulation of subretinal macrophages and the degeneration of cones, but mainly of rods. We have previously shown that Mononuclear Phagocytesderived IL-1β induces rod photoreceptor cell death during experimental subretinal inflammation and in retinal explants exposed to IL-1β but the mechanism is unknown. Methods: Retinal explants were culture in the presence of human monocytes or IL-1β and photoreceptor cell survival was analyzed by TUNEL labeling. Glutamate concentration and transcription levels of gene involved in the homeostasis of glutamate were analyzed in cell fractions of explant cultured or not in the presence of IL-1β. Glutamate receptor antagonists were evaluated for their ability to reduce photoreceptor cell death in the presence of IL1-β or monocytes. Results: We here show that IL-1β does not induce death in isolated photoreceptors, suggesting an indirect effect. We demonstrate that IL-1β leads to glutamate-induced rod photoreceptor cell death as it increases the extracellular glutamate concentrations in the retina through the inhibition of its conversion to glutamine in Müller cells, increased release from Müller cells, and diminished reuptake. The inhibition of non-NMDA receptors completely and efficiently prevented rod apoptosis in retinal explants cultured in the presence of IL-1β or, more importantly, in vivo, in a model of subretinal inflammation. Conclusions: Our study emphasizes the importance of inflammation in the deregulation of glutamate homeostasis and provides a comprehensive mechanism of action for IL-1β-induced rod degeneration.

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“…xCT mRNA expression was mainly upregulated in Müller cells, while the expression in isolated PRs remained stable (Fig. 3f), confirming previous reports [34,35].…”

Section: Il-1β Disrupts Glutamate Homeostasis In Müller Glial Cellssupporting

confidence: 90%

IL-1β induces rod degeneration through the disruption of retinal glutamate homeostasis

Charles-Messance

Blot

Couturier

et al. 2020

J Neuroinflammation

154

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“…Second, KBs are the preferred oxidative substrate for "powering" the glutamate-glutamine cycle in the environment of cerebral glucose hypometabolism seen in neurodegenerative and neuroprogressive disorders [201]. Third, and perhaps expectedly, evidence of dysfunction or dysregulation of this cycle is present in at least some regions of the brain in patients with SZ [202], MDD [203], BPD [204], AD [205], HD [206], ALS [207], and PD [208]. Moreover, impairment of this cycle is a major element in the development of disturbed glutamate homeostasis, with glutamate excitotoxicity, and reduced GABAergic signaling, which play a causative role in the pathogenesis of most if not all neurodegenerative and neuroprogressive conditions [209,210].…”

Section: Effect Of Nutritional Ketosis On the Astrocyte Glutamate-glumentioning

confidence: 99%

Nutritional ketosis as an intervention to relieve astrogliosis: Possible therapeutic applications in the treatment of neurodegenerative and neuroprogressive disorders

et al. 2020

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Nutritional ketosis, induced via either the classical ketogenic diet or the use of emulsified medium-chain triglycerides, is an established treatment for pharmaceutical resistant epilepsy in children and more recently in adults. In addition, the use of oral ketogenic compounds, fractionated coconut oil, very low carbohydrate intake, or ketone monoester supplementation has been reported to be potentially helpful in mild cognitive impairment, Parkinson’s disease, schizophrenia, bipolar disorder, and autistic spectrum disorder. In these and other neurodegenerative and neuroprogressive disorders, there are detrimental effects of oxidative stress, mitochondrial dysfunction, and neuroinflammation on neuronal function. However, they also adversely impact on neurone–glia interactions, disrupting the role of microglia and astrocytes in central nervous system (CNS) homeostasis. Astrocytes are the main site of CNS fatty acid oxidation; the resulting ketone bodies constitute an important source of oxidative fuel for neurones in an environment of glucose restriction. Importantly, the lactate shuttle between astrocytes and neurones is dependent on glycogenolysis and glycolysis, resulting from the fact that the astrocytic filopodia responsible for lactate release are too narrow to accommodate mitochondria. The entry into the CNS of ketone bodies and fatty acids, as a result of nutritional ketosis, has effects on the astrocytic glutamate–glutamine cycle, glutamate synthase activity, and on the function of vesicular glutamate transporters, EAAT, Na+, K+-ATPase, Kir4.1, aquaporin-4, Cx34 and KATP channels, as well as on astrogliosis. These mechanisms are detailed and it is suggested that they would tend to mitigate the changes seen in many neurodegenerative and neuroprogressive disorders. Hence, it is hypothesized that nutritional ketosis may have therapeutic applications in such disorders.

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“…Jackman et al [ 66 ] note that the expression of xCT in astrocytes (but not neurons or oligodendrocytes) is increased in response to IL-1β in vitro. A more recent study by the same group [ 67 ] shows that IL-1β promotes a stabilisation of xCT-specific mRNA in primary astrocyte cultures that increases its half-life. Interestingly, the authors’ data shows an increase in GSH production that is absent in cells lacking xCT.…”

Section: Astrocyte Activation and Thiol Antioxidantsmentioning

confidence: 99%

“…Furthermore, the IL-1β-mediated increase in GSH was sufficient to protect astrocytes from oxidative damage [ 68 ]. These authors also showed that IL-1β activation involves a translocation of the RNA-binding protein, HuR, from the nucleus to the cytoplasm [ 67 ]. They conclude that further investigations into the regulation of xCT should acknowledge the critical role played by this protein in the regulation of xCT expression and activity.…”

Section: Astrocyte Activation and Thiol Antioxidantsmentioning

confidence: 99%

Cysteine, Glutathione, and Thiol Redox Balance in Astrocytes

McBean

2017

Antioxidants

137

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Interleukin 1β Regulation of the System xc− Substrate-specific Subunit, xCT, in Primary Mouse Astrocytes Involves the RNA-binding Protein HuR

Cited by 14 publications

References 73 publications

IL-1β induces rod degeneration through the disruption of retinal glutamate homeostasis

IL-1β induces rod degeneration through the disruption of retinal glutamate homeostasis

Nutritional ketosis as an intervention to relieve astrogliosis: Possible therapeutic applications in the treatment of neurodegenerative and neuroprogressive disorders

Cysteine, Glutathione, and Thiol Redox Balance in Astrocytes

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