Sphingosine-1-phosphate receptor 3 promotes leukocyte rolling by mobilizing endothelial P-selectin

Nußbaum, Claudia; Bannenberg, Sarah; Keul, Petra; Gräler, Markus H.; Gonçalves-de-Albuquerque, Cassiano Felippe; Korhonen, Hanna; Lipinski, Karin von Wnuck; Heusch, Gerd; Neto, Hugo Caire de Castro Faria; Rohwedder, Ina; Göthert, Joachim R.; Prasad, Vysakh Pushpa; Haufe, Günter; Lange-Sperandio, Bäerbel; Offermanns, Stefan; Sperandio, Markus; Levkau, Bodo

doi:10.1038/ncomms7416

Cited by 83 publications

(45 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…injection of 10 mg fingolimod for just 1 h attenuated histamine-induced neutrophil recruitment to the mouse cremaster muscle (29). This was corroborated by a more recent study showing that S1P 3 , Gaq, phospholipase Cb, and Ca 2+ are employed to mobilize P-selectin in response to histamine (69). The conceptual advance in this study is the discovery that epicutaneous application of fingolimod on the skin of mice (10 mg) and humans (25 mg) significantly perturbs established inflammation.…”

Section: Discussionsupporting

confidence: 66%

Topical Application of Fingolimod Perturbs Cutaneous Inflammation

Sun

Dimasi

Pitman

et al. 2016

The Journal of Immunology

View full text Add to dashboard Cite

The prevalence of allergies, including rhinitis, eczema, and anaphylaxis, is rising dramatically worldwide. This increase is especially problematic in children who bear the greatest burden of this rising trend. Increasing evidence identifies neutrophils as primary perpetrators of the more severe and difficult to manage forms of inflammation. A newly recognized mechanism by which neutrophils are recruited during the early phase of histamine-induced inflammation involves the sphingosine kinase (SK)/sphingosine-1-phosphate axis. This study examines whether topical application of fingolimod, an established SK/sphingosine-1-phosphate antagonist already in clinical use to treat multiple sclerosis, may be repurposed to treat cutaneous inflammation. Using two mouse models of ear skin inflammation (histamine- and IgE-mediated passive cutaneous anaphylaxis) we topically applied fingolimod prophylactically, as well as after establishment of the inflammatory response, and examined ear swelling, SK activity, vascular permeability, leukocyte recruitment, and production of proinflammatory mediators. The present study reveals that when applied topically, fingolimod attenuates both immediate and late-phase responses to histamine with reduced extravasation of fluid, SK-1 activity, proinflammatory cytokine and chemokine production, and neutrophil influx and prevents ear swelling. Intravital microscopy demonstrates that histamine-induced neutrophil rolling and adhesion to the postcapillary venules in the mouse ears is significantly attenuated even after 24 h. More importantly, these effects are achievable even once inflammation is established. Translation into humans was also accomplished with epicutaneous application of fingolimod resolving histamine-induced and allergen-induced inflammatory reactions in forearm skin. Overall, this study demonstrates, to our knowledge for the first time, that fingolimod may be repurposed to treat cutaneous inflammation.

show abstract

Section: Discussionsupporting

confidence: 66%

Topical Application of Fingolimod Perturbs Cutaneous Inflammation

Sun

Dimasi

Pitman

et al. 2016

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…S1P3 plays a crucial role in endothelial inflammation and atherosclerosis, promoting leukocyte adhesion to the endothelium. 27,28 However, another report gives S1P3 a dual pro/anti-inflammatory role. 11 Our results fit with S1P3 as a proinflammatory receptor.…”

Section: Tnf-α and Apom-bound S1p Modify The Expression Of S1p-relatementioning

confidence: 99%

High-Density Lipoprotein–Associated Apolipoprotein M Limits Endothelial Inflammation by Delivering Sphingosine-1-Phosphate to the Sphingosine-1-Phosphate Receptor 1

Ruiz

Frej

Holmér

et al. 2017

ATVB

137

View full text Add to dashboard Cite

Objective-Plasma high-density lipoproteins (HDL) are potent antiatherogenic and anti-inflammatory particles. However, HDL particles are highly heterogenic in composition, and different HDL-mediated functions can be ascribed to different subclasses of HDL. Only a small HDL population contains apolipoprotein M (ApoM), which is the main plasma carrier of the bioactive lipid mediator sphingosine-1-phosphate (S1P). Vascular inflammation is modulated by S1P, but both proand anti-inflammatory roles have been ascribed to S1P. The goal of this study is to elucidate the role of ApoM and S1P in endothelial anti-inflammatory events related to HDL. Approach and Results-Aortic or brain human primary endothelial cells were challenged with tumor necrosis factor-α (TNF-α) as inflammatory stimuli. The presence of recombinant ApoM-bound S1P or ApoM-containing HDL reduced the abundance of adhesion molecules in the cell surface, whereas ApoM and ApoM-lacking HDL did not. Specifically, ApoM-bound S1P decreased vascular adhesion molecule-1 (VCAM-1) and E-selectin surface abundance but not intercellular adhesion molecule-1. Albumin, which is an alternative S1P carrier, was less efficient in inhibiting VCAM-1 than ApoM-bound S1P. The activation of the S1P receptor 1 was sufficient and required to promote anti-inflammation. Moreover, ApoM-bound S1P induced the rearrangement of the expression of S1P-related genes to counteract TNF-α. Functionally, HDL/ApoM/S1P limited monocyte adhesion to the endothelium and maintained endothelial barrier integrity under inflammatory conditions. Conclusions-ApoM-bound S1P is a key component of HDL and is responsible for several HDL-associated protective functions in the endothelium, including regulation of adhesion molecule abundance, leukocyte-endothelial adhesion, and endothelial barrier. Ruiz et al ApoM-Containing HDL Reduces Vascular Inflammation 119secretion and used by the mature ApoM protein to anchor to the phospholipid surface of HDL. 7,8 Five different membrane-bound G-protein-coupled S1P receptors (S1PRs) are known, and binding of S1P to the receptors activates multiple receptor-specific downstream signaling pathways. In this way, S1P is able to regulate several biological processes, such as immune cell trafficking, angiogenesis, endothelial cell migration, and endothelial barrier function. 9 The role of S1P in the regulation of vascular inflammation has been studied, and contradictory results have been obtained, for example, direct stimulation by S1P is reported to increase the abundance of adhesion molecules, whereas other studies [10][11][12] show that S1P inhibits tumor necrosis factor-α (TNF-α) induction of adhesion molecules, such as E-selectin, ICAM-1, or VCAM-1. 11,13The aim of this study is to characterize the role of S1P in the regulation of human endothelium inflammation taking into account that S1P is mostly bound to ApoM in plasma. Using recombinant human ApoM with or without bound S1P and isolated HDL containing or HDL lacking human ApoM (HDL +ApoM and HDL −ApoM , respectively), w...

show abstract

“…Expression of S1PR3 in endothelial cells drives leukocyte rolling by upregulating P‐selectin in a G q , phospholipase C‐dependent fashion. S1P released by mast cells acts on S1PR3 to drive leukocyte rolling and recruitment to sites of inflammation (Nussbaum et al, ). Altogether, these studies present compelling evidence that S1PR3 plays a multifactorial role in immunity by affecting dendritic cell maturation, macrophage chemotaxis and killing, and neutrophil and eosinophil recruitment, while also promoting immune cell recruitment by driving leukocyte rolling on endothelial cells.…”

Section: Introductionmentioning

confidence: 99%

Sphingosine-1-phosphate receptors and innate immunity

Bryan

Poeta

2018

Cellular Microbiology

127

View full text Add to dashboard Cite

Sphingosine-1-phosphate (S1P) is a signalling lipid that regulates many cellular processes in mammals. One well-studied role of S1P signalling is to modulate T-cell trafficking, which has a major impact on adaptive immunity. Compounds that target S1P signalling pathways are of interest for immune system modulation. Recent studies suggest that S1P signalling regulates many more cell types and processes than previously appreciated. This review will summarise current understanding of S1P signalling, focusing on recent novel findings in the roles of S1P receptors in innate immunity.

show abstract

Sphingosine-1-phosphate receptor 3 promotes leukocyte rolling by mobilizing endothelial P-selectin

Cited by 83 publications

References 69 publications

Topical Application of Fingolimod Perturbs Cutaneous Inflammation

Topical Application of Fingolimod Perturbs Cutaneous Inflammation

High-Density Lipoprotein–Associated Apolipoprotein M Limits Endothelial Inflammation by Delivering Sphingosine-1-Phosphate to the Sphingosine-1-Phosphate Receptor 1

Sphingosine-1-phosphate receptors and innate immunity

Contact Info

Product

Resources

About