Critical role of sphingosine-1-phosphate receptor 2 (S1PR2) in acute vascular inflammation

Abstract

• Endothelial S1PR2 plays a critical role in the induction of vascular permeability and vascular inflammation during endotoxemia.• S1PR2 could be a novel therapeutic target to promote vascular integrity in inflammatory vascular disorders.The endothelium, as the interface between blood and all tissues, plays a critical role in inflammation. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid, highly abundant in plasma, that potently regulates endothelial responses through interaction with its receptors (S1PRs). Here, we studied the role of S1PR2 in the regulation of the proadhesion and proinflammatory phenotype of the endothelium. By using genetic approaches and a S1PR2-specific antagonist (JTE013), we found that S1PR2 plays a key role in the permeability and inflammatory responses of the vascular endothelium during endotoxemia. Experiments with bone marrow chimeras (S1pr2 1/1 → S1pr2, and S1pr2 2/2 → S1pr2) indicate the critical role of S1PR2 in the stromal compartment, in the regulation of vascular permeability and vascular inflammation. In vitro, JTE013 potently inhibited tumor necrosis factor a-induced endothelial inflammation. Finally, we provide detailed mechanisms on the downstream signaling of S1PR2 in vascular inflammation that include the activation of the stress-activated protein kinase pathway that, together with the Rho-kinase nuclear factor kappa B pathway (NF-kB), are required for S1PR2-mediated endothelial inflammatory responses. Taken together, our data indicate that S1PR2 is a key regulator of the proinflammatory phenotype of the endothelium and identify S1PR2 as a novel therapeutic target for vascular disorders. (Blood. 2013;122(3):443-455)

An update on the biology of sphingosine 1-phosphate receptors

“…The pro-infl ammatory tendency of S1P 2 is supported by in vitro studies suggesting a paracrine feedback loop involving EC TNF ␣ induction of S1P 2 expression leading to activation of nuclear factor (NF)-B and increases in intracellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 ( 61 ). In vivo studies utilizing S1pr2 Ϫ / Ϫ mice and a model of acute infl ammation, endotoxemia, further support the conclusion that S1P 2 is an important regulator of vascular activation and therefore, permeability ( 62 ). Induction of endotoxemia in mice lacking S1pr2 in the stroma and not in the bone marrow (BM) compartment resulted in decreased vascular permeability, VCAM-1 and ICAM-1 expression, and more rapid resolution ( 62 ).…”

“…In vivo studies utilizing S1pr2 Ϫ / Ϫ mice and a model of acute infl ammation, endotoxemia, further support the conclusion that S1P 2 is an important regulator of vascular activation and therefore, permeability ( 62 ). Induction of endotoxemia in mice lacking S1pr2 in the stroma and not in the bone marrow (BM) compartment resulted in decreased vascular permeability, VCAM-1 and ICAM-1 expression, and more rapid resolution ( 62 ). Similarly, in vitro, S1P 2 actively suppressed angiogenic sprouting through leukemia-associated RhoGEF (LARG) activation of RhoC ( 63 ).…”

Sexual dimorphism in autoimmunity

“…S1PRs are GPCRs expressed in endothelium and other tissues that regulate cell survival, adherens junction assembly, migration, and barrier integrity (61-63). Several studies have indicated their role in vascular biology (64)(65)(66). Using the EAE mouse model for human MS, Cruz-Orengo and colleagues recently suggested a role for S1PR2 in MS (60).…”

Filamin A Expression Negatively Regulates Sphingosine-1-Phosphate-Induced NF-κB Activation in Melanoma Cells by Inhibition of Akt Signaling

“…In contrast, in their counterpart A7 melanoma cells that express FLNA, S1P does not activate NF-B unless the expression of FLNA is downregulated. Several previous reports suggested that S1P can activate NF-B via S1PRs (14,15,(29)(30)(31)(32)(33)(34). Although in some studies, the S1PR involved was not identified and the concentration of S1P used was too high to substantiate the involvement of S1PR-mediated events (35), others have clearly implicated S1PR1 to -3 in different cell types.…”

“…However, in HeLa cells, S1PR2, but not S1PR1 or S1PR3, was responsible for the activation of NF-B induced by extracellular S1P (14). In addition, S1PR2 induced endothelial inflammation by the activation of the Rho-ROCK (Rho-associated protein kinase) pathway leading to NF-B activation (34). Using M2 mela- noma cells, we have now provided evidence showing that both S1PR1 and S1PR2 are involved in the activation of NF-B by S1P.…”