scholarly journals Chemorepulsion by blood S1P regulates osteoclast precursor mobilization and bone remodeling in vivo

2010 ◽  
Vol 207 (13) ◽  
pp. 2793-2798 ◽  
Author(s):  
Masaru Ishii ◽  
Junichi Kikuta ◽  
Yutaka Shimazu ◽  
Martin Meier-Schellersheim ◽  
Ronald N. Germain
Keyword(s):  
Bone Remodeling ◽  
Lipid Mediator ◽  
Migratory Behavior ◽  
Bone Surface ◽  
Reciprocal Regulation ◽  
Sphingosine 1 Phosphate ◽  
S1p Receptor ◽  
Deficient Mice ◽  
High Inhibition

Sphingosine-1-phosphate (S1P), a lipid mediator enriched in blood, controls the dynamic migration of osteoclast (OC) precursors (OPs) between the blood and bone, in part via the S1P receptor 1 (S1PR1) which directs positive chemotaxis toward S1P. We show that OPs also express S1PR2, an S1P receptor which mediates negative chemotaxis (or chemorepulsion). OP-positive chemotaxis is prominent in gradients with low maximal concentrations of S1P, whereas such behavior is minimal in fields with high maximal S1P concentrations. This reverse-directional behavior is caused by S1PR2-mediated chemorepulsion acting to override S1PR1 upgradient motion. S1PR2-deficient mice exhibit moderate osteopetrosis as a result of a decrease in osteoclastic bone resorption, suggesting that S1PR2 contributes to OP localization on the bones mediated by chemorepulsion away from the blood where S1P levels are high. Inhibition of S1PR2 function by the antagonist JTE013 changed the migratory behavior of monocytoid cells, including OPs, and relieved osteoporosis in a mouse model by limiting OP localization and reducing the number of mature OCs attached to the bone surface. Thus, reciprocal regulation of S1P-dependent chemotaxis controls bone remodeling by finely regulating OP localization. This regulatory axis may be promising as a therapeutic target in diseases affecting OC-dependent bone remodeling.

The Role of Sphingosine-1-Phosphate (S1P) in Thrombopoiesis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. SCI-54-SCI-54
Author(s):  
Steffen Massberg
Keyword(s):  
Conflicts Of Interest ◽  
Multiphoton Microscopy ◽  
Lipid Mediator ◽  
Severe Thrombocytopenia ◽  
Time Loss ◽  
Sphingosine Kinase 2 ◽  
Sphingosine 1 Phosphate ◽  
S1p Receptor

Abstract Human megakaryocytes (MKs) release trillions of platelets each day into the circulation to maintain normal homeostatic platelet levels. However, the signals that control platelet biogenesis in vivo remain incompletely understood. We have recently identified that extracellular sphingosine 1-phosphate (S1P) plays a key role in thrombopoiesis. Using conditional mutants and intravital multiphoton microscopy, we demonstrate that the lipid mediator S1P serves as a critical directional cue guiding the elongation of megakaryocytic proplatelet (PP) extensions from the interstitium into bone marrow sinusoids and triggering the subsequent shedding of PPs into the blood. Correspondingly, mice lacking the S1P receptor S1pr1 develop severe thrombocytopenia caused by both formation of aberrant extravascular PPs and defective intravascular PP shedding. In contrast, activation of S1pr1 signaling leads to the prompt release of new platelets into the circulating blood. In addition to its role as an extracellular mediator, S1P can also function as a second messenger within the intracellular compartment. Correspondingly, we have demonstrated that MKs express the S1P-generating enzyme sphingosine kinase 2 (Sphk2). Sphk2 predominantly localizes to the nucleus and is the major source of intracellular S1P in MKs. Loss of Sphk2 significantly reduced intracellular S1P in MKs and downregulated the expression and activity of Src family kinases (SFKs). At the same time, loss of Sphk2 and inhibition of SFK activity resulted in defective intravascular PP shedding, the final stage of thrombopoiesis. Correspondingly, mice lacking Sphk2 in the hematopoietic system display thrombocytopenia. Collectively, our findings uncover a novel function of S1P as master regulator of efficient thrombopoiesis and might raise new therapeutic options for patients with thrombocytopenia. Disclosures No relevant conflicts of interest to declare.

Sphingosine‐1‐phosphate (S1P) induces potent anti‐inflammatory effects in vitro and in vivo by S1P receptor 4‐mediated suppression of 5‐lipoxygenase activity

2018 ◽  
Vol 33 (2) ◽  
pp. 1711-1726 ◽  
Author(s):  
Jasmin Fettel ◽  
Benjamin Kühn ◽  
Nathalie A. Guillen ◽  
Duran Sürün ◽  
Marcus Peters ◽  
...  
Keyword(s):  
Lipoxygenase Activity ◽  
Sphingosine 1 Phosphate ◽  
S1p Receptor ◽  
Anti Inflammatory

scholarly journals Endogenous EPCR/aPC-PAR1 signaling prevents inflammation-induced vascular leakage and lethality

Blood ◽  
2009 ◽  
Vol 113 (12) ◽  
pp. 2859-2866 ◽  
Author(s):  
Frank Niessen ◽  
Christian Furlan-Freguia ◽  
José A. Fernández ◽  
Laurent O. Mosnier ◽  
Francis J. Castellino ◽  
...  
Keyword(s):  
Activated Protein C ◽  
Vascular Leakage ◽  
Receptor Subtypes ◽  
Inhibitory Antibody ◽  
Vascular Effects ◽  
Signaling Specificity ◽  
Sphingosine 1 Phosphate ◽  
Protease Activated Receptor 1 ◽  
S1p Receptor

Abstract Protease activated receptor 1 (PAR1) signaling can play opposing roles in sepsis, either promoting dendritic cell (DC)–dependent coagulation and inflammation or reducing sepsis lethality due to activated protein C (aPC) therapy. To further define this PAR1 paradox, we focused on the vascular effects of PAR1 signaling. Pharmacological perturbations of the intravascular coagulant balance were combined with genetic mouse models to dissect the roles of endogenously generated thrombin and aPC during escalating systemic inflammation. Acute blockade of the aPC pathway with a potent inhibitory antibody revealed that thrombin-PAR1 signaling increases inflammation-induced vascular hyperpermeability. Conversely, aPC-PAR1 signaling and the endothelial cell PC receptor (EPCR) prevented vascular leakage, and pharmacologic or genetic blockade of this pathway sensitized mice to LPS-induced lethality. Signaling-selective aPC variants rescued mice with defective PC activation from vascular leakage and lethality. Defects in the aPC pathway were fully compensated by sphingosine 1 phosphate receptor 3 (S1P3) deficiency or by selective agonists of the S1P receptor 1 (S1P1), indicating that PAR1 signaling contributes to setting the tone for the vascular S1P1/S1P3 balance. Thus, the activating proteases and selectivity in coupling to S1P receptor subtypes determine vascular PAR1 signaling specificity in systemic inflammatory response syndromes in vivo.

Sphingosine kinase type 2 is essential for lymphopenia induced by the immunomodulatory drug FTY720

Blood ◽  
2006 ◽  
Vol 107 (4) ◽  
pp. 1454-1458 ◽  
Author(s):  
Barbara Zemann ◽  
Bernd Kinzel ◽  
Matthias Müller ◽  
Roland Reuschel ◽  
Diana Mechtcheriakova ◽  
...  
Keyword(s):  
Sphingosine Kinase ◽  
Phase 2 ◽  
Sphingosine Kinase 2 ◽  
Sphingosine 1 Phosphate ◽  
Potent Agonist ◽  
Immunomodulatory Drug ◽  
Secondary Lymphoid Organs ◽  
Deficient Mice

FTY720, a potent immunomodulatory drug in phase 2/3 clinical trials, induces rapid and reversible sequestration of lymphocytes into secondary lymphoid organs, thereby preventing their migration to sites of inflammation. As prerequisite for its function, phosphorylation of FTY720 to yield a potent agonist of the sphingosine-1-phosphate receptor S1P1 is required in vivo, catalyzed by an as-yet-unknown kinase. Here, we report on the generation of sphingosine kinase 2 (SPHK2) knockout mice and demonstrate that this enzyme is essential for FTY720 phosphate formation in vivo. Consequently, administration of FTY720 does not induce lymphopenia in SPHK2-deficient mice. After direct dosage of FTY720 phosphate, lymphopenia is only transient in this strain, indicating that SPHK2 is constantly required to maintain FTY720 phosphate levels in vivo.

scholarly journals Light Stress-Induced Increase of Sphingosine 1-Phosphate in Photoreceptors and Its Relevance to Retinal Degeneration

2019 ◽  
Vol 20 (15) ◽  
pp. 3670 ◽  
Author(s):  
Ryo Terao ◽  
Megumi Honjo ◽  
Takashi Ueta ◽  
Hideru Obinata ◽  
Takashi Izumi ◽  
...  
Keyword(s):  
Retinal Degeneration ◽  
Photoreceptor Cell ◽  
Light Exposure ◽  
Outer Nuclear Layer ◽  
Light Stress ◽  
Age Related Macular Degeneration ◽  
Lipid Mediator ◽  
Age Related ◽  
Sphingosine 1 Phosphate

Sphingosine 1-phosphate (S1P) is a potent lipid mediator that modulates inflammation and angiogenesis. In this study, we investigated the possible involvement of S1P in the pathology of light-induced retinal degeneration in vivo and in vitro. The intracellular S1P and sphingosine kinase (SphK) activity in a photoreceptor cell line (661W cells) was significantly increased by exposure to light. The enhancement of SphK1 expression was dependent on illumination, and all-trans-retinal significantly promoted SphK1 expression. S1P treatment reduced protein kinase B (Akt) phosphorylation and increased the protein expression of cleaved caspase-3, and induced photoreceptor cell apoptosis. In vivo, light exposure enhanced the expression of SphK1 in the outer segments of photoreceptors. Intravitreal injection of a SphK inhibitor significantly suppressed the thinning of the outer nuclear layer and ameliorated the attenuation of the amplitudes of a-waves and b-waves of electroretinograms during light-induced retinal degeneration. These findings imply that light exposure induces the synthesis of S1P in photoreceptors by upregulating SphK1, which is facilitated by all-trans-retinal, causing retinal degeneration. Inhibition of this enhancement may be a therapeutic target of outer retinal degeneration, including age-related macular degeneration.

scholarly journals A novel role of sphingosine 1-phosphate receptor S1pr1 in mouse thrombopoiesis

2012 ◽  
Vol 209 (12) ◽  
pp. 2165-2181 ◽  
Author(s):  
Lin Zhang ◽  
Martin Orban ◽  
Michael Lorenz ◽  
Verena Barocke ◽  
Daniel Braun ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Multiphoton Microscopy ◽  
Therapeutic Options ◽  
Lipid Mediator ◽  
Severe Thrombocytopenia ◽  
Master Regulator ◽  
Sphingosine 1 Phosphate ◽  
S1p Receptor

Millions of platelets are produced each hour by bone marrow (BM) megakaryocytes (MKs). MKs extend transendothelial proplatelet (PP) extensions into BM sinusoids and shed new platelets into the blood. The mechanisms that control platelet generation remain incompletely understood. Using conditional mutants and intravital multiphoton microscopy, we show here that the lipid mediator sphingosine 1-phosphate (S1P) serves as a critical directional cue guiding the elongation of megakaryocytic PP extensions from the interstitium into BM sinusoids and triggering the subsequent shedding of PPs into the blood. Correspondingly, mice lacking the S1P receptor S1pr1 develop severe thrombocytopenia caused by both formation of aberrant extravascular PPs and defective intravascular PP shedding. In contrast, activation of S1pr1 signaling leads to the prompt release of new platelets into the circulating blood. Collectively, our findings uncover a novel function of the S1P–S1pr1 axis as master regulator of efficient thrombopoiesis and might raise new therapeutic options for patients with thrombocytopenia.

scholarly journals Suppression of sphingosine 1-phosphate lyase retards the liver regeneration in mice after partial hepatectomy

2020 ◽  
Vol 40 (7) ◽  
Author(s):  
Yuko Kageyama ◽  
Baasanjav Uranbileg ◽  
Yoshika Kusumoto ◽  
Eri Sakai ◽  
Hitoshi Ikeda ◽  
...  
Keyword(s):  
Liver Regeneration ◽  
Partial Hepatectomy ◽  
Nuclear Antigen ◽  
Lipid Mediator ◽  
Mrna Levels ◽  
Tissue Samples ◽  
Protein Levels ◽  
Sphingosine 1 Phosphate ◽  
S1p Lyase

Abstract Background: Liver regeneration is an extremely complicated process that is regulated by a number of signaling pathways. Sphingosine 1-phosphate (S1P), a potent bioactive lipid mediator playing crucial roles in various cellular responses through its receptors, has been attracting attention in the fields of hepatology, where S1P lyase (SPL), an irreversibly degrading enzyme of S1P, reportedly has a stimulatory role in growth of hepatocellular carcinoma (HCC). Aim of the study: To examine whether SPL might play a stimulatory role in liver regeneration. Method: Using in-vivo siRNA technology, we inhibited SPL expression. Seventy percent of the liver was resected in mice as partial hepatectomy (PH). Liver tissue samples were collected and mRNA expression level of the SPL, IHC of the proliferating cell nuclear antigen (PCNA), protein levels of various proliferation factors and lipid measurements were performed in different groups. Results: The mRNA levels of SPL increased in PH mice on the third day after PH surgery. When we suppressed the expression of SPL by in-vivo siRNA, we observed a significant decline of the PCNA positive cell numbers. Furthermore, the Cyclin D1 expressions and phosphorylation of ERK also were decreased in the siSPL injected PH group. Conclusion: We verified the importance of the SPL in liver regeneration, using the mice PH model. SPL might be a potential target to facilitate liver regeneration.

scholarly journals Decreased SplenicCD4+T-Lymphocytes in Apolipoprotein M Gene Deficient Mice

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Zhigang Wang ◽  
Guanghua Luo ◽  
Yuehua Feng ◽  
Lu Zheng ◽  
Hongyao Liu ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Mrna Levels ◽  
M Gene ◽  
Apolipoprotein M ◽  
Chemotactic Protein ◽  
Murine Spleen ◽  
Sphingosine 1 Phosphate ◽  
Deficient Mice ◽  
Necrosis Factor

Spleen T-lymphocytes, especially CD4+T-cells, have been demonstrated to be involved in broad immunomodulation and host-defense activity in vivo. Apolipoprotein M gene (apoM) may have an important role in the regulation of immunoprocess and inflammation, which could be hypothesized to the apoM containing sphingosine-1-phosphate (S1P). In the present study we demonstrate that the splenic CD4+T-lymphocytes were obviously decreased in the apoM gene deficient (apoM−/−) mice compared to the wild type (apoM+/+). Moreover, these mice were treated with lipopolysaccharide (LPS) and it was found that even more pronounced decreasing CD4+T-lymphocytes occurred in the spleen compared to the apoM+/+mice. The similar phenomena were found in the ratio of CD4+/CD8+T-lymphocytes. After administration of LPS, the hepatic mRNA levels of tumor necrosis factor-α(TNF-α) and monocyte chemotactic protein-1 (MCP-1) were markedly increased; however, there were no statistical differences observed between apoM+/+mice and apoM−/−mice. The present study demonstrated that apoM might facilitate the maintenance of CD4+T-lymphocytes or could modify the T-lymphocytes subgroups in murine spleen, which may further explore the importance of apoM in the regulation of the host immunomodulation, although the detailed mechanism needs continuing investigation.

Role of sphingosine-1 phosphate in the enhancement of endothelial barrier integrity by platelet-released products

2003 ◽  
Vol 285 (1) ◽  
pp. L258-L267 ◽  
Author(s):  
Kane L. Schaphorst ◽  
Eddie Chiang ◽  
Keri N. Jacobs ◽  
Ari Zaiman ◽  
Viswanathan Natarajan ◽  
...  
Keyword(s):  
Electrical Resistance ◽  
Human Platelets ◽  
Lipid Mediator ◽  
Permeability Barrier ◽  
Barrier Dysfunction ◽  
Barrier Integrity ◽  
Enhancing Effect ◽  
Sphingosine 1 Phosphate

In vitro and in vivo evidence indicates that circulating platelets affect both vascular integrity and hemostasis. How platelets enhance the permeability barrier of the vascular endothelium is not well understood. We measured the effect of isolated human platelets on human pulmonary artery endothelial cell (EC) barrier integrity by monitoring transmonolayer electrical resistance. EC barrier function was significantly increased by the addition of platelets (∼40% maximum, 2.5 × 106platelets/ml). Platelet supernatants, derived from 2.5 × 106platelets/ml, reproduced the barrier enhancement and reversed the barrier dysfunction produced by the edemagenic agonist thrombin, which implicates a soluble barrier-promoting factor. The barrier-enhancing effect of platelet supernatants was heat stable but was attenuated by either charcoal delipidation (suggesting a vasoactive lipid mediator) or pertussis toxin, implying involvement of a Giα-coupled receptor signal transduction pathway. Sphingosine-1-phosphate (S1P), a sphingolipid that is released from activated platelets, is known to ligate G protein-coupled EC differentiation gene (EDG) receptors, increase EC electrical resistance, and reorganize the actin cytoskeleton (Garcia JG, Liu F, Verin AD, Birukova A, Dechert MA, Gerthoffer WT, Bamberg JR, and English D. J Clin Invest 108: 689–701, 2001). Infection of EC with an adenoviral vector expressing an antisense oligonucleotide directed against EDG-1 but not infection with control vector attenuated the barrier-enhancing effect of both platelet supernatants and S1P. These results indicate that a major physiologically relevant vascular barrier-protective mediator produced by human platelets is S1P.

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