Circulating Monocytes Are Reduced by Sphingosine-1-Phosphate Receptor Modulators Independently of S1P3

Lewis, Nuruddeen D.; Haxhinasto, Sokol; Anderson, Spencer; Stefanopoulos, Dimitria E.; Fogal, Steven E.; Adusumalli, Prathima; Desai, Sudha; Patnaude, Lori; Lukas, Susan; Ryan, Kelli R.; Slavin, Anthony; Brown, Marie; Modis, Louise K.

doi:10.4049/jimmunol.1201810

Cited by 60 publications

(55 citation statements)

References 38 publications

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“…In comparison, S1pr3 Ϫ / Ϫ mice on the same Apoe Ϫ / Ϫ background do not have altered development of atherosclerosis, but do have decreased monocytes and macrophages with atherosclerotic lesions ( 101 ). In WT mice, treatment with FTY720 results in decreased circulating monocytes; however, use of the S1P 1/4/5 agonist, BAF312, yielded similar results, both at homeostasis and during EAE, indicating that S1P 3 is not the sole regulator of monocyte circulation ( 104 ). This could be a cell subtype-specifi c effect, or dependent on environment, as local administration of FTY720 appeared to enhance recruitment of anti-infl ammatory pro-angiogenic monocytes ( 105 ).…”

Section: Immune Systemmentioning

confidence: 75%

An update on the biology of sphingosine 1-phosphate receptors

Blaho

Hla

2014

Journal of Lipid Research

443

403

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This article is available online at http://www.jlr.org during development and ageing. S1P 1 , S1P 2 , and S1P 3 are essentially ubiquitously expressed, whereas expression of S1P 4 and S1P 5 are highly restricted to distinct cell types ( 4 ).Production of S1P can be initiated by external or internal signals, which lead to activation of the biosynthetic pathway beginning with metabolism of membrane SM to ceramide by SMases ( 5, 6 ). Ceramide, an important signaling molecule itself, can be metabolized by ceramidase to sphingosine (Sph) ( 7 ). Sph is then phosphorylated by one of two Sph kinases (Sphks), Sphk1 or Sphk2, resulting in S1P genesis ( 8-10 ) ( Fig. 1 ).Although there are proposed intracellular roles for S1P, it is often transported out of the cell where it can act in an autocrine or paracrine manner on S1PRs ( 11, 12 ). Transport out of the cell may occur via several transporters; however, the only bona fi de transporter to date is spinster 2, which is also capable of FTY720 (fi ngolimod/Gilenya; Novartis) export (13)(14)(15)(16)(17)(18)(19)(20)(21)(22). Once outside of the cell, S1P can bind to two known carriers, albumin or ApoM ( 6, 23, 24 ) ( Fig. 1 ). Approximately 35% of plasma S1P is bound to albumin and 65% to ApoM, which is found on a small percentage ( ‫ف‬ 5%) of HDL particles ( 24 ). This ApoM+HDL-bound S1P has been proposed as a primary contributor to the vasoprotective properties of HDLs ( 25-27 ). How albumin or ApoM deliver S1P to specifi c S1PRs has yet to be characterized. AGONISTS AND ANTAGONISTSThere are several well-characterized agonists and antagonists of S1PRs; however, most compounds have been diAbstract Sphingosine 1-phosphate (S1P) is a membranederived lysophospholipid that acts primarily as an extracellular signaling molecule. Signals initiated by S1P are transduced by five G protein-coupled receptors, named S1P 1-5 . Cellular and temporal expression of the S1P receptors (S1PRs) determine their specifi c roles in various organ systems, but they are particularly critical for regulation of the cardiovascular, immune, and nervous systems, with the most well-known contributions of S1PR signaling being modulation of vascular barrier function, vascular tone, and regulation of lymphocyte traffi cking. However, our knowledge of S1PR biology is rapidly increasing as they become attractive therapeutic targets in several diseases, such as chronic infl ammatory pathologies, autoimmunity, and cancer. Understanding how the S1PRs regulate interactions between biological systems will allow for greater effi cacy in this novel therapeutic strategy as well as characterization of complex physiological networks. Because of the rapidly expanding body of research, this review will focus on the most recent advances in S1PRs. Sphingosine 1-phosphate [2 S -amino-1-(dihydrogen phosphate)-4E-octadecene-1,3 R -diol] (S1P) is a simple membrane-derived lysophospholipid with regulatory roles in almost all facets of mammalian biology ( 1 ). Concentrations of S1P in blood and lymph plasmas are high, in the high...

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Section: Immune Systemmentioning

confidence: 75%

An update on the biology of sphingosine 1-phosphate receptors

Blaho

Hla

2014

Journal of Lipid Research

443

403

View full text Add to dashboard Cite

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“…EAE was induced as described [19]. Female C57BL/6 mice were subcutaneously injected with 100 µg of MOG35–55 (myelin oligodendrocyte glycoprotein; AnaSpec) in IFA (incomplete Freund's adjuvant; Difco) containing 250 µg of Mycobacterium tuberculosis (Difco).…”

Section: Methodsmentioning

confidence: 99%

A GPBAR1 (TGR5) Small Molecule Agonist Shows Specific Inhibitory Effects on Myeloid Cell Activation In Vitro and Reduces Experimental Autoimmune Encephalitis (EAE) In Vivo

et al. 2014

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GPBAR1 is a G protein-coupled receptor that is activated by certain bile acids and plays an important role in the regulation of bile acid synthesis, lipid metabolism, and energy homeostasis. Recent evidence suggests that GPBAR1 may also have important effects in reducing the inflammatory response through its expression on monocytes and macrophages. To further understand the role of GPBAR1 in inflammation, we generated a novel, selective, proprietary GPBAR1 agonist and tested its effectiveness at reducing monocyte and macrophage activation in vitro and in vivo. We have used this agonist, together with previously described agonists to study agonism of GPBAR1, and shown that they can all induce cAMP and reduce TLR activation-induced cytokine production in human monocytes and monocyte-derived macrophages in vitro. Additionally, through the usage of RNA sequencing (RNA-Seq), we identified a select set of genes that are regulated by GPBAR1 agonism during LPS activation. To further define the in vivo role of GPBAR1 in inflammation, we assessed GPBAR1 expression and found high levels on circulating mouse monocytes. Agonism of GPBAR1 reduced LPS-induced cytokine production in mouse monocytes ex vivo and serum cytokine levels in vivo. Agonism of GPBAR1 also had profound effects in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis, where monocytes play an important role. Mice treated with the GPBAR1 agonist exhibited a significant reduction in the EAE clinical score which correlated with reduced monocyte and microglial activation and reduced trafficking of monocytes and T cells into the CNS. These data confirm the importance of GPBAR1 in controlling monocyte and macrophage activation in vivo and support the rationale for selective agonists of GPBAR1 in the treatment of inflammatory diseases.

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“…Biomaterial-based release of chemotactic molecules and signaling molecules provides a method to spatially control these processes and generate gradients in vivo . While secreted protein signals such as stromal cell derived factor-1α (SDF-1α) [4], fractalkine [5], monocyte chemotactic protein-1 (MCP-1) [6] and vascular endothelial growth factor (VEGF) [7] are well-known chemotactic and growth cues, lipid mediators such as sphingosine-1-phosphate (S1P) have more recently become recognized for their essential roles in spatial guidance, signaling, and ability to modify the sensitivity of cells to other chemokines and growth factors [8–11]. S1P plays a critical role in microvascular physiology and the movement of cells between blood and tissue spaces both physiologically and pathophysiologically [12] making it an attractive signaling axis to target therapeutically.…”

Section: Introductionmentioning

confidence: 99%

Engineering in vivo gradients of sphingosine-1-phosphate receptor ligands for localized microvascular remodeling and inflammatory cell positioning

et al. 2014

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Biomaterial-mediated controlled release of soluble signaling molecules is a tissue engineering approach to spatially control processes of inflammation, microvascular remodeling, and host cell recruitment and to generate biochemical gradients in vivo. Lipid mediators, such as sphingosine 1-phosphate (S1P), are recognized for their essential roles in spatial guidance, signaling, and highly regulated endogenous gradients. S1P and pharmacological analogs such as FTY720 are therapeutically attractive targets for their critical roles in the trafficking of cells between blood and tissue spaces both physiologically and pathophysiologically. However, the interaction of locally delivered sphingolipids with the complex metabolic networks controlling the flux of lipid species in inflamed tissue has yet to be elucidated. In this study, complementary in vitro and in vivo approaches are investigated to identify relationships between polymer composition, drug release kinetics, S1P metabolic activity, signaling gradients, and spatial positioning of circulating cells around poly lactic-co-glycolic acid (PLGA) biomaterials. Results demonstrate that biomaterial-based gradients of S1P are short-lived in the tissue due to degradation by S1P lyase, an enzyme that irreversibly degrades intracellular S1P. On the other hand, in vivo gradients of the more stable compound, FTY720 enhance microvascular remodeling by selectively recruiting an anti-inflammatory subset of monocytes (S1P3high) to the biomaterial. Results highlight the need to better understand the endogenous balance of lipid import/export machinery and lipid kinase/phosphatase activity in order to design biomaterial products that spatially control the innate immune environment to maximize regenerative potential.

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Circulating Monocytes Are Reduced by Sphingosine-1-Phosphate Receptor Modulators Independently of S1P3

Cited by 60 publications

References 38 publications

An update on the biology of sphingosine 1-phosphate receptors

An update on the biology of sphingosine 1-phosphate receptors

A GPBAR1 (TGR5) Small Molecule Agonist Shows Specific Inhibitory Effects on Myeloid Cell Activation In Vitro and Reduces Experimental Autoimmune Encephalitis (EAE) In Vivo

Engineering in vivo gradients of sphingosine-1-phosphate receptor ligands for localized microvascular remodeling and inflammatory cell positioning

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