Pathway specific modulation of <scp>S1P1</scp> receptor signalling in rat and human astrocytes

Healy, Luke M.; Sheridan, Graham K.; Pritchard, Adam J.; Rutkowska, Aleksandra; Müllershausen, Florian; Dev, Kumlesh K.

doi:10.1111/bph.12207

Cited by 45 publications

(60 citation statements)

References 33 publications

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“…Binding of S1P receptor agonists, including FTY720 and CYM, to S1P receptors causes internalization and may cause functional antagonism, persistent signaling or both. 12,50,51 The ways in which internalization, degradation, and sustained signaling collectively regulate S1P receptor function are not yet understood. Further studies are needed to fully elucidate the molecular mechanism by which the S1P agonists act.…”

Section: Discussionmentioning

confidence: 99%

The S1P1 receptor-selective agonist CYM-5442 reduces the severity of acute GVHD by inhibiting macrophage recruitment

Cheng

Lin

et al. 2014

Cell Mol Immunol

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FTY720, an agonist for four of the five known sphingosine-1-phosphate (S1P) receptors, has been reported to inhibit acute graft-versus-host disease (aGVHD). Because FTY720 functions through multiple S1P receptors, the mechanism of action through one or more of these receptors may account for its side effects. Thus, more selective S1P receptor modulators are needed to evaluate the roles of different S1P receptors and their therapeutic efficacies. In this study, we investigated the effect of an S1P 1 -selective agonist, CYM-5442, on the progression of aGVHD. We showed that CYM-5442 significantly inhibited but did not prevent aGVHD. CYM-5442 did not affect the infiltration of the donor T cells into the target organs, while the number of macrophages in GVHD organs was significantly reduced by CYM-5442 treatment. In vivo proliferation assays showed that the proliferation of macrophages was not suppressed by CYM-5442. Further studies using human endothelial cells demonstrated that CYM-5442 treatment downregulated CCL2 and CCL7 expression in endothelial cells, therefore reducing the migration of monocytes, from which tissue macrophages originate. Our data demonstrate the therapeutic efficacy of an S1P 1 -selective agonist in aGVHD and its possible mechanism of action. The results suggest that further investigations are needed regarding CYM-5442 as a potential therapeutic regimen for aGVHD.

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Section: Discussionmentioning

confidence: 99%

The S1P1 receptor-selective agonist CYM-5442 reduces the severity of acute GVHD by inhibiting macrophage recruitment

Cheng

Lin

et al. 2014

Cell Mol Immunol

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“…Moreover, these data are in agreement with our suppression data with CYM-5442 (which has an IC 50 for Gi/Go signaling of 1.2 nM) and support a non-Gi/Go-mediated mechanism of suppression. We next investigated the involvement of the S1PR1 C terminus using an inhibitory peptide mimic of the S1PR1 C terminus consisting of an HIV Tat sequence coupled to amino acids that correspond to the C terminus of S1PR1 (17). The IFN-α response to CpG-A was similar in pDCs treated with either CYM-5442 alone or with CYM-5442 and a control scrambled C-terminal peptide (control peptide) (Fig.…”

Section: Significancementioning

confidence: 99%

S1PR1-mediated IFNAR1 degradation modulates plasmacytoid dendritic cell interferon-α autoamplification

Teijaro

Studer

Leaf

et al. 2016

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

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Blunting immunopathology without abolishing host defense is the foundation for safe and effective modulation of infectious and autoimmune diseases. Sphingosine 1-phosphate receptor 1 (S1PR1) agonists are effective in treating infectious and multiple autoimmune pathologies; however, mechanisms underlying their clinical efficacy are yet to be fully elucidated. Here, we uncover an unexpected mechanism of convergence between S1PR1 and interferon alpha receptor 1 (IFNAR1) signaling pathways. Activation of S1PR1 signaling by pharmacological tools or endogenous ligand sphingosine-1 phosphate (S1P) inhibits type 1 IFN responses that exacerbate numerous pathogenic conditions. Mechanistically, S1PR1 selectively suppresses the type I IFN autoamplification loop in plasmacytoid dendritic cells (pDCs), a specialized DC subset, for robust type I IFN release. S1PR1 agonist suppression is pertussis toxin-resistant, but inhibited by an S1PR1 C-terminal-derived transactivating transcriptional activator (Tat)-fusion peptide that blocks receptor internalization. S1PR1 agonist treatment accelerates turnover of IFNAR1, suppresses signal transducer and activator of transcription 1 (STAT1) phosphorylation, and downmodulates total STAT1 levels, thereby inactivating the autoamplification loop. Inhibition of S1P-S1PR1 signaling in vivo using the selective antagonist Ex26 significantly elevates IFN-α production in response to CpG-A. Thus, multiple lines of evidence demonstrate that S1PR1 signaling sets the sensitivity of pDC amplification of IFN responses, thereby blunting pathogenic immune responses. These data illustrate a lipid G-protein coupled receptor (GPCR)-IFNAR1 regulatory loop that balances effective and detrimental immune responses and elevated endogenous S1PR1 signaling. This mechanism will likely be advantageous in individuals subject to a range of inflammatory conditions. sphingosine 1-phosphate | S1PR1 | plasmacytoid dendritic cell | interferon-α | IFNAR1

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“…Human, rat and mouse astrocytes were cultured as we have described before (Healy et al, 2013;Rutkowska et al, 2015). BV2 microglia were cultured in DMEM supplemented with 2% FBS (Labtech) and 1% penicillin/ streptomycin (Sigma) at 37°C and 5% CO 2 .…”

Section: Astrocyte and Cerebellar Slice Culturesmentioning

confidence: 99%

Galactosylsphingosine (psychosine)-induced demyelination is attenuated by sphingosine 1-phosphate signalling

O’Sullivan

Dev

2015

Journal of Cell Science

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Globoid cell leukodystrophy (Krabbe disease) is a rare infantile neurodegenerative disorder. Krabbe disease is caused by deficiency in the lysosomal enzyme galactocerebrosidase (GALC) resulting in accumulation, in the micromolar range, of the toxic metabolite galactosylsphingosine ( psychosine) in the brain. Here we find that psychosine induces human astrocyte cell death probably via an apoptotic process in a concentration-and time-dependent manner (EC50∼15 μM at 4 h). We show these effects of psychosine are attenuated by pre-treatment with the sphingosine 1-phosphate receptor agonist pFTY720 (fingolimod) (IC50∼100 nM). Psychosine (1 μM, 10 μM) also enhances LPS-induced (EC50∼100 ng/ml) production of pro-inflammatory cytokines in mouse astrocytes, which is also attenuated by pFTY720 (1 μM). Most notably, for the first time, we show that psychosine, at a concentration found in the brains of patients with Krabbe disease (EC50∼100 nM), directly induces demyelination in mouse organotypic cerebellar slices in a manner that is independent of pro-inflammatory cytokine response and that pFTY720 (0.1 nM) significantly inhibits. These results support the idea that psychosine is a pathogenic agent in Krabbe disease and suggest that sphingosine 1-phosphate signalling could be a potential drug target for this disorder.

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Pathway specific modulation of S1P1 receptor signalling in rat and human astrocytes

Cited by 45 publications

References 33 publications

The S1P1 receptor-selective agonist CYM-5442 reduces the severity of acute GVHD by inhibiting macrophage recruitment

The S1P1 receptor-selective agonist CYM-5442 reduces the severity of acute GVHD by inhibiting macrophage recruitment

S1PR1-mediated IFNAR1 degradation modulates plasmacytoid dendritic cell interferon-α autoamplification

Galactosylsphingosine (psychosine)-induced demyelination is attenuated by sphingosine 1-phosphate signalling

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