Sphingosine 1-phosphate in coagulation and inflammation

Abstract

Sphingosine 1-phosphate (S1P) is a lipid mediator produced from sphingomyelin by the sequential enzymatic actions of sphingomyelinase, ceramidase, and sphingosine kinase. Five subtypes of cell surface G-protein-coupled receptors, S1P1–5, mediate the actions of S1P in various organs systems, most notably cardiovascular, immune, and central nervous systems. S1P is enriched in blood and lymph but is present at much lower concentrations in interstitial fluids of tissues. This vascular S1P gradient is important for the regulation of trafficking of various immune cells. FTY720, which was recently approved for the treatment of relapsing-remitting multiple sclerosis, potently sequesters lymphocytes into lymph nodes by functionally antagonizing the activity of the S1P1 receptor. S1P also plays critical roles in the vascular barrier integrity, thereby regulating inflammation, tumor metastasis, angiogenesis, and atherosclerosis. Recent studies have also revealed the involvement of S1P signaling in coagulation and in tumor necrosis factor α-mediated signaling. This review highlights the importance of S1P signaling in these inflammatory processes as well as the contribution of each receptor subtype, which exhibits both cooperative and redundant functions.

S1P 2 /G 12/13 Signaling Negatively Regulates Macrophage Activation and Indirectly Shapes the Atheroprotective B1-Cell Population

“…S1P 2 is widely expressed and has been implicated in the regulation of neuronal excitability, angiogenesis, and immune cell functions. 44 The intracellular effects induced by S1P 2 activation are complex: both G 12/13 -dependent activation of RhoA and G i/o -/G q/11 -dependent effects such as Rac1 activation have been described. 44 Interestingly, a dysbalance in the activation of RhoA and Rac1 has also been discussed as an underlying factor in the negative regulatory role of S1P 2 / G 12/13 /RhoA-signaling in germinal center B-cell growth 45 or the inhibitory effect of S1P 2 on macrophage migration.…”

“…44 The intracellular effects induced by S1P 2 activation are complex: both G 12/13 -dependent activation of RhoA and G i/o -/G q/11 -dependent effects such as Rac1 activation have been described. 44 Interestingly, a dysbalance in the activation of RhoA and Rac1 has also been discussed as an underlying factor in the negative regulatory role of S1P 2 / G 12/13 /RhoA-signaling in germinal center B-cell growth 45 or the inhibitory effect of S1P 2 on macrophage migration. [46][47][48] In addition, we found evidence for a role of S1P-dependent Gα 12/13 activation in the facilitation of cAMP production.…”

Translational Pharmacokinetic Modeling of Fingolimod (FTY720) as a Paradigm Compound Subject to Sphingosine Kinase-Mediated Phosphorylation

“…Another important difference between the rat and human model is that saturable binding to a high affinity/low capacity binding site on a protein in the plasma was identified in humans, whereas this could not be identified in rats. This could represent saturable binding to high-density lipoprotein, because in human plasma, more than half of S1P is found in the high-density (Obinata and Hla, 2012) and S1P and fingolimod-P are structurally related. As a result, the fingolimod-P blood/plasma exposure ratio was constant over the observed dose range (the ratio was about 1) in rats, whereas this ratio increased with higher doses from 0.95 for a dose of 0.5 mg to 1.9 for a dose of 5 mg at steady state in human.…”

Sphingosine 1-phosphate signalling

“…In mouse and zebrafish models, multiple S1P receptors (S1P 1-3 ) coordinately regulate vascular development (Kono et al, 2004;Obinata and Hla, 2012). Recent evidence, however, points towards an important role for S1pr1 in maintaining flow-dependent vascular network stability.…”