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Journal ArticleDOI

Enhancement of capillary leakage and restoration of lymphocyte egress by a chiral S1P 1 antagonist in vivo

TL;DR: Chemical modulation reveals differences in S1P-S1P1 'set points' among tissues and highlights both mechanistic advantages (lymphocyte sequestration) and risks (pulmonary edema) of therapeutic intervention.
Abstract: Sphingosine 1-phosphate (S1P, 1) regulates vascular barrier and lymphoid development, as well as lymphocyte egress from lymphoid organs, by activating high-affinity S1P1 receptors. We used reversible chemical probes (i) to gain mechanistic insights into S1P systems organization not accessible through genetic manipulations and (ii) to investigate their potential for therapeutic modulation. Vascular (but not airway) administration of the preferred R enantiomer of an in vivo‐active chiral S1P1 receptor antagonist induced loss of capillary integrity in mouse skin and lung. In contrast, the antagonist did not affect the number of constitutive blood lymphocytes. Instead, alteration of lymphocyte trafficking and phenotype required supraphysiological elevation of S1P1 tone and was reversed by the antagonist. In vivo two-photon imaging of lymph nodes confirmed requirements for obligate agonism, and the data were consistent with the presence of a stromal barrier mechanism for gating lymphocyte egress. Thus, chemical modulation reveals differences in S1P-S1P1 ‘set points’ among tissues and highlights both mechanistic advantages (lymphocyte sequestration) and risks (pulmonary edema) of therapeutic intervention. Chemical agents provide powerful tools for dissecting complex physiological functions mediated through diverse receptor subtypes. In particular, selective agonist and antagonist pairs that are active in vivo have the distinct advantage of enabling acute, reversible modulation of molecular function while circumventing the developmental compensations that can arise in gene deletion studies. We have targeted this approach to the signaling pathway mediated by S1P and have thereby showed that in vivo–active reversible chemical tools can be used to address a series of mechanistic and therapeutic questions. S1P is a pleiotropic autocrine and paracrine signaling lipid 1 that mediates graded rheostat control of numerous physiological functions through a family of G protein–coupled receptors. Small variations in ligand concentration are amplified by selective high-affinity receptors to acutely regulate vital functions such as heart rate 2,3 ,v ascular and stromal barrier integrity 4 and lymphocyte egress 5 .T he functioning of S1P receptors in the maintenance and modulation of biological barrier activity is of profound biological importance and has therapeutic implications 4 , including prevention of transplant rejection and treatment of multiple sclerosis and perhaps adult respiratory distress syndrome as well 6 .

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Citations
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Journal ArticleDOI
TL;DR: A more integrated overview of the key role of these signalling lipids in inflammation, cancer and metabolic disease is attempted, and emerging strategies for therapeutic intervention are discussed.
Abstract: Signalling lipids such as eicosanoids, phosphoinositides, sphingolipids and fatty acids control important cellular processes, including cell proliferation, apoptosis, metabolism and migration. Extracellular signals from cytokines, growth factors and nutrients control the activity of a key set of lipid-modifying enzymes: phospholipases, prostaglandin synthase, 5-lipoxygenase, phosphoinositide 3-kinase, sphingosine kinase and sphingomyelinase. These enzymes and their downstream targets constitute a complex lipid signalling network with multiple nodes of interaction and cross-regulation. Imbalances in this network contribute to the pathogenesis of human disease. Although the function of a particular signalling lipid is traditionally studied in isolation, this review attempts a more integrated overview of the key role of these signalling lipids in inflammation, cancer and metabolic disease, and discusses emerging strategies for therapeutic intervention.

1,134 citations

Journal ArticleDOI
TL;DR: The discovery and development of fingolimod is described, which was approved by the US Food and Drug Administration in September 2010 as a first-line treatment for relapsing forms of multiple sclerosis, thereby becoming the first oral disease-modifying therapy to be approved for multiple sclerosis in the United States.
Abstract: The discovery of fingolimod (FTY720/Gilenya; Novartis), an orally active immunomodulatory drug, has opened up new approaches to the treatment of multiple sclerosis, the most common inflammatory disorder of the central nervous system. Elucidation of the effects of fingolimod--mediated by the modulation of sphingosine 1-phosphate (S1P) receptors--has indicated that its therapeutic activity could be due to regulation of the migration of selected lymphocyte subsets into the central nervous system and direct effects on neural cells, particularly astrocytes. An improved understanding of the biology of S1P receptors has also been gained. This article describes the discovery and development of fingolimod, which was approved by the US Food and Drug Administration in September 2010 as a first-line treatment for relapsing forms of multiple sclerosis, thereby becoming the first oral disease-modifying therapy to be approved for multiple sclerosis in the United States.

1,075 citations

Journal ArticleDOI
13 Apr 2007-Science
TL;DR: Separate sources provide S1P to plasma and lymph to help lymphocytes exit the low-S1P environment of lymphoid organs, and disruption of compartmentalized S 1P signaling is a plausible mechanism by which S1p-receptor-1 agonists function as immunosuppressives.
Abstract: Lymphocytes require sphingosine-1-phosphate (S1P) receptor-1 to exit lymphoid organs, but the source(s) of extracellular S1P and whether S1P directly promotes egress are unknown. By using mice in which the two kinases that generate S1P were conditionally ablated, we find that plasma S1P is mainly hematopoietic in origin, with erythrocytes a major contributor, whereas lymph S1P is from a distinct radiation-resistant source. Lymphocyte egress from thymus and secondary lymphoid organs was markedly reduced in kinase-deficient mice. Restoration of S1P to plasma rescued egress to blood but not lymph, and the rescue required lymphocyte expression of S1P-receptor-1. Thus, separate sources provide S1P to plasma and lymph to help lymphocytes exit the low-S1P environment of lymphoid organs. Disruption of compartmentalized S1P signaling is a plausible mechanism by which S1P-receptor-1 agonists function as immunosuppressives.

861 citations

Journal ArticleDOI
TL;DR: There is substantial evidence that sphingosine 1-phosphate (S1P) is involved in cancer and the potential for new therapeutics designed to alter S1P signalling and function in cancer is examined.
Abstract: There is substantial evidence that sphingosine 1-phosphate (S1P) is involved in cancer. S1P regulates processes such as inflammation, which can drive tumorigenesis; neovascularization, which provides cancer cells with nutrients and oxygen; and cell growth and survival. This occurs at multiple levels and involves S1P receptors, sphingosine kinases, S1P phosphatases and S1P lyase. This Review summarizes current research findings and examines the potential for new therapeutics designed to alter S1P signalling and function in cancer.

760 citations

Journal ArticleDOI
TL;DR: Current understanding of how Sphingosine-1-phosphate promotes exit from the secondary lymphoid organs and thymus is summarized and how FTY720, a drug that targets S1P receptors and is approved for the treatment of multiple sclerosis, causes immune suppression is examined.
Abstract: Much has been learned about how cells enter lymphoid tissues. But how do they leave? Sphingosine-1-phosphate (S1P) has emerged over the past decade as a central mediator of lymphocyte egress. In this review, we summarize the current understanding of how S1P promotes exit from the secondary lymphoid organs and thymus. We review what is known about additional requirements for emigration and summarize the mostly distinct requirements for exit from the bone marrow. Egress from lymphoid organs is limited during immune responses, and we examine how this regulation works. There is accumulating evidence for roles of S1P in directing immune cell behavior within lymphoid tissues. How such actions can fit together with the egress-promoting role of S1P is discussed. Finally, we examine current understanding of how FTY720, a drug that targets S1P receptors and is approved for the treatment of multiple sclerosis, causes immune suppression.

715 citations

References
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Journal ArticleDOI
22 Jan 2004-Nature
TL;DR: It is established that S1P1 is essential for lymphocyte recirculation and that it regulates egress from both thymus and peripheral lymphoid organs.
Abstract: Adaptive immunity depends on T-cell exit from the thymus and T and B cells travelling between secondary lymphoid organs to survey for antigens. After activation in lymphoid organs, T cells must again return to circulation to reach sites of infection; however, the mechanisms regulating lymphoid organ exit are unknown. An immunosuppressant drug, FTY720, inhibits lymphocyte emigration from lymphoid organs, and phosphorylated FTY720 binds and activates four of the five known sphingosine-1-phosphate (S1P) receptors1,2,3,4. However, the role of S1P receptors in normal immune cell trafficking is unclear. Here we show that in mice whose haematopoietic cells lack a single S1P receptor (S1P1; also known as Edg1) there are no T cells in the periphery because mature T cells are unable to exit the thymus. Although B cells are present in peripheral lymphoid organs, they are severely deficient in blood and lymph. Adoptive cell transfer experiments establish an intrinsic requirement for S1P1 in T and B cells for lymphoid organ egress. Furthermore, S1P1-dependent chemotactic responsiveness is strongly upregulated in T-cell development before exit from the thymus, whereas S1P1 is downregulated during peripheral lymphocyte activation, and this is associated with retention in lymphoid organs. We find that FTY720 treatment downregulates S1P1, creating a temporary pharmacological S1P1-null state in lymphocytes, providing an explanation for the mechanism of FTY720-induced lymphocyte sequestration. These findings establish that S1P1 is essential for lymphocyte recirculation and that it regulates egress from both thymus and peripheral lymphoid organs.

2,400 citations


"Enhancement of capillary leakage an..." refers background in this paper

  • ...and abnormalities in the development of the immune syste...

    [...]

Journal ArticleDOI
TL;DR: The evolutionarily conserved actions of the sphingolipid metabolite, sphingosine-1-phosphate (S1P), in yeast, plants and mammals have shown that it has important functions.
Abstract: The evolutionarily conserved actions of the sphingolipid metabolite, sphingosine-1-phosphate (S1P), in yeast, plants and mammals have shown that it has important functions. In higher eukaryotes, S1P is the ligand for a family of five G-protein-coupled receptors. These S1P receptors are differentially expressed, coupled to various G proteins, and regulate angiogenesis, vascular maturation, cardiac development and immunity, and are important for directed cell movement.

2,008 citations


"Enhancement of capillary leakage an..." refers background in this paper

  • ...We have characterized selective, reversible chemical tools that acutely alter the set point of S1P-S1P 1 rheostat...

    [...]

Journal ArticleDOI
12 Apr 2002-Science
TL;DR: It is shown that lymphocyte trafficking is altered by the lysophospholipid sphingosine-1-phosphate (S1P) and by a phosphoryl metabolites of the immunosuppressive agent FTY720.
Abstract: Blood lymphocyte numbers, essential for the development of efficient immune responses, are maintained by recirculation through secondary lymphoid organs. We show that lymphocyte trafficking is altered by the lysophospholipid sphingosine-1-phosphate (S1P) and by a phosphoryl metabolite of the immunosuppressive agent FTY720. Both species were high-affinity agonists of at least four of the five S1P receptors. These agonists produce lymphopenia in blood and thoracic duct lymph by sequestration of lymphocytes in lymph nodes, but not spleen. S1P receptor agonists induced emptying of lymphoid sinuses by retention of lymphocytes on the abluminal side of sinus-lining endothelium and inhibition of egress into lymph. Inhibition of lymphocyte recirculation by activation of S1P receptors may result in therapeutically useful immunosuppression.

1,641 citations


"Enhancement of capillary leakage an..." refers background in this paper

  • ...Reverse pharmacology using compounds of unknown molecular interaction that induce disappearance of lymphocytes from the blood and that proved to be S1P receptor agonists first identified the S1P 1 receptor as a target capable of inducing clinically useful immunosuppressio...

    [...]

Journal ArticleDOI
TL;DR: The data reveal Edg-1 to be the first G protein-coupled receptor required for blood vessel formation and show that sphingolipid signaling is essential during mammalian development.
Abstract: Sphingolipid signaling pathways have been implicated in many critical cellular events. Sphingosine-1-phosphate (SPP), a sphingolipid metabolite found in high concentrations in platelets and blood, stimulates members of the endothelial differentiation gene (Edg) family of G protein-coupled receptors and triggers diverse effects, including cell growth, survival, migration, and morphogenesis. To determine the in vivo functions of the SPP/Edg signaling pathway, we disrupted the Edg1 gene in mice. Edg1(-/-) mice exhibited embryonic hemorrhage leading to intrauterine death between E12.5 and E14.5. Vasculogenesis and angiogenesis appeared normal in the mutant embryos. However, vascular maturation was incomplete due to a deficiency of vascular smooth muscle cells/pericytes. We also show that Edg-1 mediates an SPP-induced migration response that is defective in mutant cells due to an inability to activate the small GTPase, Rac. Our data reveal Edg-1 to be the first G protein-coupled receptor required for blood vessel formation and show that sphingolipid signaling is essential during mammalian development.

1,159 citations


"Enhancement of capillary leakage an..." refers background in this paper

  • ...Genetic deletions of S1P 1 have revealed the receptor's essential endothelial functions in arterial smooth muscle cell migration; absence of S1P 1 results in embryonic lethalit...

    [...]

Journal ArticleDOI
23 Mar 2006-Nature
TL;DR: Treatment with the IFN-α/β inducer polyinosine polycytidylic acid inhibited egress by a mechanism that was partly lymphocyte-intrinsic, and observations indicate that CD69 forms a complex with and negatively regulates S1P1 and that it functions downstream ofIFN- α/β, and possibly other activating stimuli, to promote lymphocyte retention in lymphoid organs.
Abstract: Naive lymphocytes continually enter and exit lymphoid organs in a recirculation process that is essential for immune surveillance. During immune responses, the egress process can be shut down transiently. When this occurs locally it increases lymphocyte numbers in the responding lymphoid organ; when it occurs systemically it can lead to immunosuppression as a result of the depletion of recirculating lymphocytes. Several mediators of the innate immune system are known to cause shutdown, including interferon alpha/beta (IFN-alpha/beta) and tumour necrosis factor, but the mechanism has been unclear. Here we show that treatment with the IFN-alpha/beta inducer polyinosine polycytidylic acid (hereafter 'poly(I:C)') inhibited egress by a mechanism that was partly lymphocyte-intrinsic. The transmembrane C-type lectin CD69 was rapidly induced and CD69-/- cells were poorly retained in lymphoid tissues after treatment with poly(I:C) or infection with lymphocytic choriomeningitis virus. Lymphocyte egress requires sphingosine 1-phosphate receptor-1 (S1P1), and IFN-alpha/beta was found to inhibit lymphocyte responsiveness to S1P. By contrast, CD69-/- cells retained S1P1 function after exposure to IFN-alpha/beta. In coexpression experiments, CD69 inhibited S1P1 chemotactic function and led to downmodulation of S1P1. In a reporter assay, S1P1 crosslinking led to co-crosslinking and activation of a CD69-CD3zeta chimaera. CD69 co-immunoprecipitated with S1P1 but not the related receptor, S1P3. These observations indicate that CD69 forms a complex with and negatively regulates S1P1 and that it functions downstream of IFN-alpha/beta, and possibly other activating stimuli, to promote lymphocyte retention in lymphoid organs.

1,046 citations

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