Targeting sphingosine 1-phosphate (S1P) levels and S1P receptor functions for therapeutic immune interventions.

Sphingosine 1-phosphate (S1P) is an important regulator of many different immune functions including lymphocyte circulation, antigen presentation, and T cell development. It stimulates five G protein-coupled receptors designated S1P(1-5), which are also expressed by immune cells. S1P receptors couple to different heterotrimeric G proteins including G alpha i, q, and 12/13, and elicit cellular signalling events by activating the small GTPases Rac and Rho and protein kinases Akt, ERK, and JNK, and by inducing cellular calcium flux and inhibiting cAMP accumulation, amongst others. S1P is the exit signal for lymphocytes leaving lymphoid organs and present in blood and lymph at high nanomolar concentrations due to the S1P-producing activity of sphingosine kinases (SK). The S1P-degrading enzyme S1P-lyase maintains low amounts of S1P in lymphoid organs. Disrupting this concentration difference by S1P receptor agonists and antagonists like FTY720, SEW2871, and VPC23019, by an anti-S1P antibody, or by inhibiting the S1P-lyase has therapeutic potential for autoimmune diseases like multiple sclerosis (MS) and rheumatoid arthritis and for many other disorders like cancer, fibrosis, inflammation, macular degeneration, diabetic retinopathy, and glaucoma. This report aims to provide a brief overview of concepts, approaches, pharmaceutical compounds, and targets that are currently used to modulate S1P-driven immune functions.