The sphingosine-1-phosphate receptor-1 antagonist, W146, causes early and short-lasting peripheral blood lymphopenia in mice

Tarrasón, Gema; Aulí, Mariona; Mustafa, Sanam; Dolgachev, Vladislav; Domènech, Maria Teresa; Prats, Neus; Domínguez, María; López, Rosa; Aguilar, Núria; Calbet, Marta; Pont, Mercè; Milligan, Graeme; Kunkel, Steven L.; Godessart, Núria

doi:10.1016/j.intimp.2011.07.004

Cited by 60 publications

(45 citation statements)

References 26 publications

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“…Of note, the beneficial effect of RP101075 on neurological outcomes and brain edema was blocked by W146, a selective RP101075 antagonist. [38][39][40] Together with the reduced cellular infiltration and inflammatory cytokine expression after RP101075 treatment, these results support the notion that modulation of S1PR1 is sufficient to suppress brain inflammation and provide protection in ICH. The superior pharmacological features along with its efficacy may qualify RP101075 as a promising candidate for future ICH investigations.…”

Section: Discussionsupporting

confidence: 68%

“…1 2 % Evans blue (2 ml/kg) was injected intravenously 2 h prior to sacrifice. The ipsilateral hemisphere 38 was weighed on an electronic balance (with an accuracy of 0.1 mg) and homogenized into a test tube with 5 ml of 39 formamide (Sigma, USA), then incubated in a 60 °C water bath for 72 h. After centrifugation at 1000 x rpm for 40 5 min, the supernatants were collected for testing. A microplate reader (Thermo Scientific, Varioskan Flash, USA) 41 was used (λ = 450, 570 nm) to measure the OD of the supernatant and the standards (80, 40, 20, 10, 5, 2.5, 1.25, 42 0.625, 0.3125, 0.15625 μg /ml).…”

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confidence: 99%

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Selective Sphingosine-1-Phosphate Receptor 1 Modulation Attenuates Experimental Intracerebral Hemorrhage

Sun

Shen

Han

et al. 2016

Stroke

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Intracerebral hemorrhage (ICH) is a devastating disease, which accounts for ≈10% to 15% of strokes with high mortality and morbidity.1,2 Effective treatments for ICH remain sparse.1 Accumulating evidence has demonstrated that brain inflammation provoked by microglia and infiltrating lymphocytes exacerbates ICH-induced brain injury.3 After ICH, brain-intrinsic microglia are the first immune responder and followed by inflammatory infiltrates such as neutrophils, monocytes, macrophages, and subsets of lymphocytes. 4,5 Activation of these cellular components together with factors they produce and cell death products, further contribute to brain inflammation, which results in the development of perihematomal edema.3-7 Perihematomal edema can aggravate the mass effect and secondary brain injury through subsequent oligemia and inflammatory insults.1,8 Edema, as a surrogate marker for inflammation in ICH, 1,9,10 and the persistence of perihematomal edema after ictus makes it amenable for intervention.1 Thus, targeting inflammation could be a viable approach for treating ICH.Sphingosine-1-phosphate (S1P) is a ligand for 5 G-proteincoupled receptors: S1P receptors 1 to 5 (S1PR1-5) are responsible for numerous cell-intrinsic and extrinsic activities. 11,12 Fingolimod (FTY720, Glenya), an oral therapy for multiple sclerosis (MS), is a S1PR modulator that binds to S1PR1, 3, 4, and 5. The beneficial effects of fingolimod in MS may be mediated by S1PR1 expressed on lymphocytes, vascular endothelia, neurons, and glia.11 Recent preclinical and clinical studies have demonstrated that fingolimod can attenuate neurodeficits and brain edema in ICH. [13][14][15][16][17][18] However, it remains unclear whether immune modulations via S1PR1 are sufficient for fingolimod to provide Background and Purpose-Preclinical studies and a proof-of-concept clinical study have shown that sphingosine-1-phosphate receptor (S1PR) modulator, fingolimod, improves the clinical outcome of intracerebral hemorrhage (ICH). However, the specific subtype of the S1PRs through which immune modulation provides protection in ICH remains unclear. In addition, fingolimod-induced adverse effects could limit its use in patients with stroke because of interactions with other S1PR subtypes, particularly with S1PR3. RP101075 is a selective S1PR1 agonist with superior cardiovascular safety profile. In this study, we investigated the impact of RP101075 treatment in a mouse model of ICH. Methods-ICH was induced by injection of autologous blood in 294 male C57BL/6J and Rag2 −/− mice. ICH mice randomly received vehicle, RP101075, or RP101075 plus S1PR1 antagonist W146 by daily oral gavage for three consecutive days, starting from 30 minutes after surgery. Neurodeficits, brain edema, brain infiltration of immune cells, blood-brain barrier integrity, and cell death were assessed after ICH. Results-RP101075 significantly attenuated neurological deficits and reduced brain edema in ICH mice. W146 blocked the effects of RP101075 on neurodeficits and brain edema. RP101075 reduced th...

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Section: Discussionsupporting

confidence: 68%

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confidence: 99%

Selective Sphingosine-1-Phosphate Receptor 1 Modulation Attenuates Experimental Intracerebral Hemorrhage

Sun

Shen

Han

et al. 2016

Stroke

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“…In this regard, recent reevaluation of W146 activities revealed that W146 is a potent inducer of early and shortlasting peripheral blood lymphopenia when high plasma levels are produced by i.p. administration (45), supporting the notion that maintenance of high in vivo S1P 1 antagonistic activities is required for inducing lymphocyte sequestration.…”

Section: Discussionsupporting

confidence: 63%

Amelioration of Collagen-Induced Arthritis by a Novel S1P1 Antagonist with Immunomodulatory Activities

Fujii

Hirayama

Ohtake

et al. 2012

The Journal of Immunology

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Sphingosine 1-phosphate (S1P) regulates lymphocyte trafficking through the type 1 sphingosine 1-phosphate receptor (S1P1) and participates in many pathological conditions, including autoimmune diseases. We developed a novel S1P1-selective antagonist, TASP0277308, which is structurally unrelated to S1P. This antagonist competitively inhibited S1P-induced cellular responses, such as chemotaxis and receptor internalization. Furthermore, differing from previously reported S1P1 antagonists, TASP0277308 demonstrated in vivo activities to induce lymphopenia, a block in T cell egress from the thymus, displacement of marginal zone B cells, and upregulation of CD69 expression on both T and B cells, all of which recapitulate phenotypes of S1P1-deficient lymphocytes. In a mouse collagen-induced arthritis model, TASP0277308 significantly suppressed the development of arthritis, even after the onset of disease. These findings provide the first chemical evidence to our knowledge that S1P1 antagonism is responsible for immunosuppression in the treatment of autoimmune diseases and also resolve the discrepancies between genetic and chemical studies on the functions of S1P1 in lymphocytes.

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“…The W146 enhances vascular leakage and promotes hematogenous spread of tumor at maximal plasma concentrations of 90 nM. In contrast, peak plasma levels of ϳ20 uM of W146 are required for short lasting lymphopenic effects (W146 physiological half life is ϳ73 min) (45). These highly significant differences in plasma concentrations are adequate for vascular leakage effects but significantly low for immunomodulatory effects.…”

Section: Discussionmentioning

confidence: 99%

Host endothelial S1PR₁ regulation of vascular permeability modulates tumor growth

Sarkisyan

Nguyen

Felding

et al. 2014

American Journal of Physiology-Cell Physiology

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Understanding vascular growth and maturation in developing tumors has important implications for tumor progression, spread, and ultimately host survival. Modulating the signaling of endothelial G protein-coupled receptors (GPCRs) in blood and lymphatic vessels can enhance or limit tumor progression. Sphingosine 1-phosphate receptor 1 (S1PR1) is a GPCR for circulating lysophospholipid S1P that is highly expressed in blood and lymphatic vessels. Using the S1PR1- enhanced green fluorescent protein (eGFP) mouse model in combination with intravital imaging and pharmacologic modulation of S1PR1 signaling, we show that boundary conditions of high and low S1PR1 signaling retard tumor progression by enhancing or destabilizing neovasculature integrity, respectively. In contrast, midrange S1PR1 signaling, achieved by receptor antagonist titration, promotes abundant growth of small, organized vessels and thereby enhances tumor progression. Furthermore, in vivo S1PR1 antagonism supports lung colonization by circulating tumor cells. Regulation of endothelial S1PR1 dynamically controls vascular integrity and maturation and thus modulates angiogenesis, tumor growth, and hematogenous metastasis.

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The sphingosine-1-phosphate receptor-1 antagonist, W146, causes early and short-lasting peripheral blood lymphopenia in mice

Cited by 60 publications

References 26 publications

Selective Sphingosine-1-Phosphate Receptor 1 Modulation Attenuates Experimental Intracerebral Hemorrhage

Selective Sphingosine-1-Phosphate Receptor 1 Modulation Attenuates Experimental Intracerebral Hemorrhage

Amelioration of Collagen-Induced Arthritis by a Novel S1P1 Antagonist with Immunomodulatory Activities

Host endothelial S1PR₁ regulation of vascular permeability modulates tumor growth

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The sphingosine-1-phosphate receptor-1 antagonist, W146, causes early and short-lasting peripheral blood lymphopenia in mice

Cited by 60 publications

References 26 publications

Selective Sphingosine-1-Phosphate Receptor 1 Modulation Attenuates Experimental Intracerebral Hemorrhage

Selective Sphingosine-1-Phosphate Receptor 1 Modulation Attenuates Experimental Intracerebral Hemorrhage

Amelioration of Collagen-Induced Arthritis by a Novel S1P1 Antagonist with Immunomodulatory Activities

Host endothelial S1PR1 regulation of vascular permeability modulates tumor growth

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Host endothelial S1PR₁ regulation of vascular permeability modulates tumor growth