scholarly journals Mechanism of sphingosine 1-phosphate clearance from blood

2020 ◽  
Vol 477 (5) ◽  
pp. 925-935 ◽  
Author(s):  
Yugesh Kharel ◽  
Tao Huang ◽  
Anita Salamon ◽  
Thurl E. Harris ◽  
Webster L. Santos ◽  
...  
Keyword(s):  
Immune Cell ◽  
General Mechanism ◽  
Concentration Gradients ◽  
Sphingosine Kinase 2 ◽  
Sphingosine 1 Phosphate ◽  
Degradative Enzymes ◽  
High Altitude Acclimatization ◽  
Endothelial Integrity ◽  
S1p Lyase

The interplay of sphingosine 1-phosphate (S1P) synthetic and degradative enzymes as well as S1P exporters creates concentration gradients that are a fundamental to S1P biology. Extracellular S1P levels, such as in blood and lymph, are high relative to cellular S1P. The blood-tissue S1P gradient maintains endothelial integrity while local S1P gradients influence immune cell positioning. Indeed, the importance of S1P gradients was recognized initially when the mechanism of action of an S1P receptor agonist used as a medicine for multiple sclerosis was revealed to be inhibition of T-lymphocytes’ recognition of the high S1P in efferent lymph. Furthermore, the increase in erythrocyte S1P in response to hypoxia influences oxygen delivery during high altitude acclimatization. However, understanding of how S1P gradients are maintained is incomplete. For example, S1P is synthesized but is only slowly metabolized by blood yet circulating S1P turns over quickly by an unknown mechanism. Prompted by the counterintuitive observation that blood S1P increases markedly in response to inhibition S1P synthesis (by sphingosine kinase 2 (SphK2)), we studied mice wherein several tissues were made deficient in either SphK2 or S1P degrading enzymes. Our data reveal a mechanism whereby S1P is de-phosphorylated at the hepatocyte surface and the resulting sphingosine is sequestered by SphK phosphorylation and in turn degraded by intracellular S1P lyase. Thus, we identify the liver as the primary site of blood S1P clearance and provide an explanation for the role of SphK2 in this process. Our discovery suggests a general mechanism whereby S1P gradients are shaped.

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.

The role of the lysophospholipid sphingosine 1-phosphate in immune cell biology

2006 ◽  
Vol 54 (4) ◽  
pp. 239-251 ◽  
Author(s):  
Henrik von Wenckstern ◽  
Karsten Zimmermann ◽  
Burkhard Kleuser
Keyword(s):  
Cell Biology ◽  
Immune Cell ◽  
Sphingosine 1 Phosphate

scholarly journals The role of sphingolipids in endothelial barrier function

2015 ◽  
Vol 396 (6-7) ◽  
pp. 681-691 ◽  
Author(s):  
Peter L. Jernigan ◽  
Amy T. Makley ◽  
Richard S. Hoehn ◽  
Michael J. Edwards ◽  
Timothy A. Pritts
Keyword(s):  
Barrier Function ◽  
Biologically Active ◽  
Endothelial Barrier ◽  
Endothelial Barrier Function ◽  
Physiologic Function ◽  
Sphingosine 1 Phosphate ◽  
Endothelial Integrity ◽  
Pathologic Processes ◽  
Immense Potential

Abstract Sphingolipids are a ubiquitous family of essential lipids with an increasingly understood role as biologically active mediators in numerous physiologic and pathologic processes. Two particular sphingolipid species, sphingosine-1-phosphate and ceramide, and their metabolites interact both directly and indirectly with endothelial cells to regulate vascular permeability. Sphingosine-1-phosphate generally augments endothelial integrity while ceramide tends to promote vascular leak, and a tight balance between the two is necessary to maintain normal physiologic function. The mechanisms by which sphingolipids regulate endothelial barrier function are complex and occur through multiple different pathways, and disruptions or imbalances in these pathways have been implicated in a number of specific disease processes. With improved understanding of sphingolipid biology, endothelial function, and the interactions between the two, several targets for therapeutic intervention have emerged and there is immense potential for further advancement in this field.

scholarly journals A2B Adenosine Receptors and Sphingosine 1-Phophate Signaling Cross-Talk in Oligodendrogliogenesis

2021 ◽  
Vol 15 ◽  
Author(s):  
Elisabetta Coppi ◽  
Francesca Cencetti ◽  
Federica Cherchi ◽  
Martina Venturini ◽  
Chiara Donati ◽  
...  
Keyword(s):  
Adenosine Receptors ◽  
Adult Life ◽  
Oligodendrocyte Progenitor Cells ◽  
Voltage Dependent ◽  
Sphingosine 1 Phosphate ◽  
Demyelinating Disorders ◽  
S1p Lyase ◽  
Stimulation Of

Oligodendrocyte-formed myelin sheaths allow fast synaptic transmission in the brain. Impairments in the process of myelination, or demyelinating insults, might cause chronic diseases such as multiple sclerosis (MS). Under physiological conditions, remyelination is an ongoing process throughout adult life consisting in the differentiation of oligodendrocyte progenitor cells (OPCs) into mature oligodendrocytes (OLs). During pathological events, this process fails due to unfavorable environment. Adenosine and sphingosine kinase/sphingosine 1-phosphate signaling axes (SphK/S1P) play important roles in remyelination processes. Remarkably, fingolimod (FTY720), a sphingosine analog recently approved for MS treatment, plays important roles in OPC maturation. We recently demonstrated that the selective stimulation of A2B adenosine receptors (A2BRs) inhibit OPC differentiation in vitro and reduce voltage-dependent outward K+ currents (IK) necessary to OPC maturation, whereas specific SphK1 or SphK2 inhibition exerts the opposite effect. During OPC differentiation A2BR expression increases, this effect being prevented by SphK1/2 blockade. Furthermore, selective silencing of A2BR in OPC cultures prompts maturation and, intriguingly, enhances the expression of S1P lyase, the enzyme responsible for irreversible S1P catabolism. Finally, the existence of an interplay between SphK1/S1P pathway and A2BRs in OPCs was confirmed since acute stimulation of A2BRs activates SphK1 by increasing its phosphorylation. Here the role of A2BR and SphK/S1P signaling during oligodendrogenesis is reviewed in detail, with the purpose to shed new light on the interaction between A2BRs and S1P signaling, as eventual innovative targets for the treatment of demyelinating disorders.

scholarly journals The Functional Role of Sphingosine Kinase 2

2021 ◽  
Vol 8 ◽  
Author(s):  
Rocio Diaz Escarcega ◽  
Louise D. McCullough ◽  
Andrey S. Tsvetkov
Keyword(s):  
Sphingosine Kinase ◽  
Telomere Maintenance ◽  
Sphingosine Kinase 1 ◽  
Lipid Molecule ◽  
Nuclear Signaling ◽  
Sphingosine Kinase 2 ◽  
Sphingosine 1 Phosphate ◽  
Associated Conditions ◽  
Health And Disease

Sphingosine-1-phosphate (S1P) is a bioactive lipid molecule that is present in all eukaryotic cells and plays key roles in various extracellular, cytosolic, and nuclear signaling pathways. Two sphingosine kinase isoforms, sphingosine kinase 1 (SPHK1) and sphingosine kinase 2 (SPHK2), synthesize S1P by phosphorylating sphingosine. While SPHK1 is a cytoplasmic kinase, SPHK2 is localized to the nucleus, endoplasmic reticulum, and mitochondria. The SPHK2/S1P pathway regulates transcription, telomere maintenance, mitochondrial respiration, among many other processes. SPHK2 is under investigation as a target for treating many age-associated conditions, such as cancer, stroke, and neurodegeneration. In this review, we will focus on the role of SPHK2 in health and disease.

scholarly journals The Role of Platelets in Cancer Pathophysiology: Focus on Malignant Glioma

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 569 ◽  
Author(s):  
Sascha Marx ◽  
Yong Xiao ◽  
Marcel Baschin ◽  
Maximilian Splittstöhser ◽  
Robert Altmann ◽  
...  
Keyword(s):  
Malignant Glioma ◽  
Immune Cells ◽  
Potential Role ◽  
Immune Cell ◽  
Malignant Gliomas ◽  
Cell Communication ◽  
Distant Metastases ◽  
Sphingosine 1 Phosphate ◽  
The Central Nervous System

The link between thrombocytosis and malignancy has been well known for many years and its associations with worse outcomes have been reported mainly for solid tumors. Besides measuring platelet count, it has become popular to assess platelet function in the context of malignant diseases during the last decade. Malignant gliomas differ tremendously from malignancies outside the central nervous system because they virtually never form distant metastases. This review summarizes the current understanding of the platelet–immune cell communication and its potential role in glioma resistance and progression. Particularly, we focus on platelet-derived proinflammatory modulators, such as sphingosine-1-phosphate (S1P). The multifaceted interaction with immune cells puts the platelet into an interesting perspective regarding the recent advances in immunotherapeutic approaches in malignant glioma.

scholarly journals Subcellular distribution of FTY720 and FTY720-phosphate in immune cells – another aspect of Fingolimod action relevant for therapeutic application

2015 ◽  
Vol 396 (6-7) ◽  
pp. 795-802 ◽  
Author(s):  
Matthias Schröder ◽  
Olga Arlt ◽  
Helmut Schmidt ◽  
Andrea Huwiler ◽  
Carlo Angioni ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Immune Cells ◽  
Subcellular Distribution ◽  
Immune Cell ◽  
Lipid Mediator ◽  
Sphingosine Kinase 2 ◽  
Relapsing Remitting ◽  
Sphingosine 1 Phosphate ◽  
Original Cell ◽  
Relapsing Remitting Multiple Sclerosis

Abstract FTY720 (Fingolimod; Gilenya®) is an immune-modulatory prodrug which, after intracellular phosphorylation by sphingosine kinase 2 (SphK2) and export, mimics effects of the endogenous lipid mediator sphingosine-1-phosphate. Fingolimod has been introduced to treat relapsing-remitting multiple sclerosis. However, little has been published about the immune cell membrane penetration and subcellular distribution of FTY720 and FTY720-P. Thus, we applied a newly established LC-MS/MS method to analyze the subcellular distribution of FTY720 and FTY720-P in subcellular compartments of spleen cells of wild type, SphK1- and SphK2-deficient mice. These studies demonstrated that, when normalized to the original cell volume and calculated on molar basis, FTY720 and FTY720-P dramatically accumulated several hundredfold within immune cells reaching micromolar concentrations. The amount and distribution of FTY720 was differentially affected by SphK1- and SphK2-deficiency. On the background of recently described relevant intracellular FTY720 effects in the nanomolar range and the prolonged application in multiple sclerosis, this data showing a substantial intracellular accumulation of FTY720, has to be considered for benefit/risk ratio estimates.

scholarly journals Beyond Immune Cell Migration: The Emerging Role of the Sphingosine-1-phosphate Receptor S1PR4 as a Modulator of Innate Immune Cell Activation

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Catherine Olesch ◽  
Christian Ringel ◽  
Bernhard Brüne ◽  
Andreas Weigert
Keyword(s):  
Immune Cells ◽  
Cell Activation ◽  
Immune Cell ◽  
Diverse Range ◽  
Therapeutic Implications ◽  
Receptor Repertoire ◽  
Sphingosine 1 Phosphate ◽  
Specific Outcome ◽  
Important Regulator

The sphingolipid sphingosine-1-phosphate (S1P) emerges as an important regulator of immunity, mainly by signaling through a family of five specific G protein-coupled receptors (S1PR1–5). While S1P signaling generally has the potential to affect not only trafficking but also differentiation, activation, and survival of a diverse range of immune cells, the specific outcome depends on the S1P receptor repertoire expressed on a given cell. Among the S1PRs, S1PR4 is specifically abundant in immune cells, suggesting a major role of the S1P/S1PR4 axis in immunity. Recent studies indeed highlight its role in activation of immune cells, differentiation, and, potentially, trafficking. In this review, we summarize the emerging data that support a major role of S1PR4 in modulating immunity in humans and mice and discuss therapeutic implications.

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