Sphingosine-1-Phosphate Signaling in Immune Cells and Inflammation: Roles and Therapeutic Potential

Abstract

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite involved in many critical cell processes. It is produced by the phosphorylation of sphingosine by sphingosine kinases (SphKs) and exported out of cells via transporters such as spinster homolog 2 (Spns2). S1P regulates diverse physiological processes by binding to specific G protein-binding receptors, S1P receptors (S1PRs) 1–5, through a process coined as “inside-out signaling.” The S1P concentration gradient between various tissues promotes S1PR1-dependent migration of T cells from secondary lymphoid organs into the lymphatic and blood circulation. S1P suppresses T cell egress from and promotes retention in inflamed peripheral tissues. S1PR1 in T and B cells as well as Spns2 in endothelial cells contributes to lymphocyte trafficking. FTY720 (Fingolimod) is a functional antagonist of S1PRs that induces systemic lymphopenia by suppression of lymphocyte egress from lymphoid organs. In this review, we summarize previous findings and new discoveries about the importance of S1P and S1PR signaling in the recruitment of immune cells and lymphocyte retention in inflamed tissues. We also discuss the role of S1P-S1PR1 axis in inflammatory diseases and wound healing.

Survival benefit of sphingosin‐1‐phosphate and receptors expressions in breast cancer patients

“…SPHK1 increases S1P levels in the local environment and induced proliferation signaling 29. On the other hand, SPHK2 presented and form S1P in the nucleus 30. In our study, we added S1P in vitro which increases extracellular S1P concentration to mimic Sphk1 pathway to induce proliferation signals.…”

Compounds of the sphingomyelin-ceramide-glycosphingolipid pathways as secondary messenger molecules: new targets for novel therapies for fatty liver disease and insulin resistance

“…Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are the most common causes of liver disorders. Both metabolic changes and inflammatory pathways are altered in these patients (10,17,18,109,113,116,120). Patients with NASH committed to inflammation early in the disease and continue to have progressive inflammation over time, leading to fibrogenesis and liver cirrhosis.…”

“…Portal and systemic PL profiling defined the NASH signature in morbid obesity (9,10,39). Lipidomic analysis showed a reduction of PC in the steatotic liver; however, PC homeostasis is an important factor for alcoholic steatohepatitis (ASH)/NASH.…”

Analysing the effect of I1 imidazoline receptor ligands on DSS-induced acute colitis in mice

“…Although in the majority of these studies other molecular targets than IRs were found to mediate the anti-inflammatory action of imidazoline drugs, the intriguing hypothesis of Molderings et al (2007a, b) that I1-IRs may belong to the family of S1P receptors and represent mixtures of homo and/or heterodimers of S1P1-3 receptors suggests that also pharmacological modulation of I1-IRs may result in reduced inflammation. Namely, it is well-established that S1P1-3 receptors are essential for immune cell trafficking and lymphocyte egress from lymphoid organs (Aoki et al 2016), and S1P receptor modulators ameliorate the severity of inflammation in different diseases, including colitis (Daniel et al 2007; Deguchi et al 2006;Snider et al 2009). Therefore, it can be hypothesized that I1-IR ligands may interfere with normal S1P signaling, which in turn might induce anti-inflammatory action.…”

“…Because S1P receptors have pivotal role in the regulation of immune cell trafficking (reviewed e.g. by Aoki et al 2016;Chi 2011;Cyster and Schwab 2012), it can be speculated that I1-IR ligands may have immunomodulatory properties, similarly to the S1P receptor modulator FTY720, which has potent antiinflammatory effect in various clinical and preclinical inflammatory conditions, including dextran sulfate sodium (DSS)-and 2,4,6-trinitrobenzenesulfonic acid (TNBS)-evoked murine colitis (Daniel et al 2007;Deguchi et al 2006). In short, these data suggest that imidazoline drugs, such as moxonidine and rilmenidine, may have beneficial (and yet unrecognized) effects in patients with inflammatory diseases, including colitis.…”