Differential involvement of TNFα in hypoxic suppression of astrocyte glutamate transporters

Boycott, Hannah E.; Wilkinson, Jenny A.; Boyle, John P.; Pearson, Hugh A.; Peers, Chris

doi:10.1002/glia.20673

Cited by 39 publications

(38 citation statements)

References 46 publications

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“…As shown in T cells and cardiomyocytes, inhibition of any of these components may be sufficient to severely limit transcription of target genes, although the activity of each is insufficient to direct transcription on its own (33). Interestingly, EAAT2 levels were recently shown to exhibit down-regulation in response to TNF␣ through a mechanism involving NFB (98). Note then that the CN/NFAT pathway could regulate EAAT2 at multiple levels: by increasing levels of TNF␣, as shown in Fig.…”

Section: Il-mediated Immune/inflammatory Signaling and The Cn/nfatmentioning

confidence: 89%

Interleukin-1β-dependent Signaling between Astrocytes and Neurons Depends Critically on Astrocytic Calcineurin/NFAT Activity

Sama

Mathis

Furman

et al. 2008

Journal of Biological Chemistry

119

161

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Interleukin-1␤ (IL-1␤) and the Ca2؉ /calmodulin-dependent protein phosphatase, calcineurin, have each been shown to play an important role in neuroinflammation. However, whether these signaling molecules interact to coordinate immune/inflammatory processes and neurodegeneration has not been investigated. Here, we show that exogenous application of IL-1␤ (10 ng/ml) recruited calcineurin/NFAT (nuclear factor of activated T cells) activation in primary astrocyte-enriched cultures within minutes, through a pathway involving IL-1 receptors and L-type Ca 2؉ channels. Adenovirus-mediated delivery of the NFAT inhibitor, VIVIT, suppressed the IL-1␤-dependent induction of several inflammatory mediators and/or markers of astrocyte activation, including tumor necrosis factor ␣, granulocyte/macrophage colony-stimulating factor, and vimentin. Expression of an activated form of calcineurin in one set of astrocyte cultures also triggered the release of factors that, in turn, stimulated NFAT activity in a second set of "naive" astrocytes. This effect was prevented when calcineurin-expressing cultures co-expressed VIVIT, suggesting that the calcineurin/ NFAT pathway coordinates positive feedback signaling between astrocytes. In the presence of astrocytes and neurons, 48-h delivery of IL-1␤ was associated with several excitotoxic effects, including NMDA receptor-dependent neuronal death, elevated extracellular glutamate, and hyperexcitable synaptic activity. Each of these effects were reversed or ameliorated by targeted delivery of VIVIT to astrocytes. IL-1␤ also caused an NFAT-dependent reduction in excitatory amino acid transporter levels, indicating a possible mechanism for IL-1␤-mediated excitotoxicity. Taken together, the results have potentially important implications for the propagation and maintenance of neuroinflammatory signaling processes associated with many neurodegenerative conditions and diseases.

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Section: Il-mediated Immune/inflammatory Signaling and The Cn/nfatmentioning

confidence: 89%

Interleukin-1β-dependent Signaling between Astrocytes and Neurons Depends Critically on Astrocytic Calcineurin/NFAT Activity

Sama

Mathis

Furman

et al. 2008

Journal of Biological Chemistry

119

161

View full text Add to dashboard Cite

show abstract

“…However, others have described a down-regulation of GLT-1 by inflammatory mediators. For instance, a role was assigned to TNF-α during the hypoxia-mediated suppression of GLT-1 in astrocytes [29]. These inconsistencies may originate from the diversity of models, pathologies and culture methods tested (e.g.…”

Section: Discussionmentioning

confidence: 99%

Differential Regulation of Glutamate Transporter Subtypes by Pro-Inflammatory Cytokine TNF-α in Cortical Astrocytes from a Rat Model of Amyotrophic Lateral Sclerosis

et al. 2014

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Dysregulation of the astroglial glutamate transporters GLAST and GLT-1 has been implicated in several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) where a loss of GLT-1 protein expression and activity is reported. Furthermore, the two principal C-terminal splice variants of GLT-1 (namely GLT-1a and GLT-1b) show altered expression ratio in animal models of this disease. Considering the putative link between inflammation and excitotoxicity, we have here characterized the influence of TNF-α on glutamate transporters in cerebral cortical astrocyte cultures from wild-type rats and from a rat model of ALS (hSOD1G93A). Contrasting with the down-regulation of GLAST, a 72 h treatment with TNF-α substantially increased the expression of GLT-1a and GLT-1b in both astrocyte cultures. However, as the basal level of GLT-1a appeared considerably lower in hSOD1G93A astrocytes, its up-regulation by TNF-α was insufficient to recapitulate the expression observed in wild-type astrocytes. Also the glutamate uptake activity after TNF-α treatment was lower for hSOD1G93A astrocytes as compared to wild-type astrocytes. In the presence of the protein synthesis inhibitor cycloheximide, TNF-α did not influence GLT-1 isoform expression, suggesting an active role of dynamically regulated protein partners in the adaptation of astrocytes to the inflammatory environment. Confirming the influence of inflammation on the control of glutamate transmission by astrocytes, these results shed light on the regulation of glutamate transporter isoforms in neurodegenerative disorders.

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“…61,62 Similarly to hypoxia, the inflammatory cytokine TNF␣ also reduces EAAT2 expression in astrocytes. 63 It is possible that enhancing the EAAT2 abundance in astrocytes could reduce excitotoxicity in stroke and neurodegenerative diseases. A screen to identify drugs that induce EAAT2 demonstrated that the ␤-lactam antibiotics, especially ceftriaxone (CFX), increase the expression of EAAT2 in organotypic spinal cord slice cultures.…”

Section: Astrocytes Edema and Volume Regulation In Strokementioning

confidence: 99%

Targeting Astrocytes for Stroke Therapy

2010

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Summary: Stroke remains a major health problem and is a leading cause of death and disability. Past research and neurotherapeutic clinical trials have targeted the molecular mechanisms of neuronal cell death during stroke, but this approach has uniformly failed to reduce stroke-induced damage or to improve functional recovery. Beyond the intrinsic molecular mechanisms inducing neuronal death during ischemia, survival and function of astrocytes is absolutely required for neuronal survival and for functional recovery after stroke. Many functions of astrocytes likely improve neuronal viability during stroke. For example, uptake of glutamate and release of neurotrophins enhances neuronal viability during ischemia. Under certain conditions, however, astrocyte function may compromise neuronal viability. For example, astrocytes may produce inflammatory cytokines or toxic mediators, or may release glutamate. The only clinical neurotherapeutic trial for stroke that specifically targeted astrocyte function focused on reducing release of S-100␤ from astrocytes, which becomes a neurotoxin when present at high levels. Recent work also suggests that astrocytes, beyond their influence on cell survival, also contribute to angiogenesis, neuronal plasticity, and functional recovery in the several days to weeks after stroke. If these delayed functions of astrocytes could be targeted for enhancing stroke recovery, it could contribute importantly to improving stroke recovery. This review focuses on both the positive and the negative influences of astrocytes during stroke, especially as they may be targeted for translation to human trials.

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Differential involvement of TNFα in hypoxic suppression of astrocyte glutamate transporters

Cited by 39 publications

References 46 publications

Interleukin-1β-dependent Signaling between Astrocytes and Neurons Depends Critically on Astrocytic Calcineurin/NFAT Activity

Interleukin-1β-dependent Signaling between Astrocytes and Neurons Depends Critically on Astrocytic Calcineurin/NFAT Activity

Differential Regulation of Glutamate Transporter Subtypes by Pro-Inflammatory Cytokine TNF-α in Cortical Astrocytes from a Rat Model of Amyotrophic Lateral Sclerosis

Targeting Astrocytes for Stroke Therapy

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