The role of sphingosine 1-phosphate in immunity and sepsis.

Sphingosine 1-phosphate (S1P) is a lipid metabolite with intra- and extracellular signalling properties. It activates five G protein-coupled cell surface receptors designated S1P-receptors type 1-5 (S1P1-5) that transmit extracellular signals into cells, and it modulates intracellular signalling as a cofactor. The analysis of sphingosine kinases (SphK) type 1 and 2, the key enzymes for S1P production, in different infection models point to an important role for the activation of different immune cells like macrophages, mast cells, and dendritic cells. S1P additionally influences local and systemic lymphocyte circulation and positioning, the vascular tone, and blood pressure. Modulation of S1P-mediated signalling pathways therefore results either in local immune cell activation or systemic immune suppression, or both. Pharmacological approaches that modulate certain S1P-mediated signalling pathways while leaving others untouched appear to be promising new avenues for next generation pharmaceuticals. This review summarizes current strategies to modulate S1P signalling for immune intervention with the clear focus on the specificity of the different principles applied. Known local and systemic effects of S1P on immunity are discussed as potential pharmaceutical targets to combat immune and autoimmune diseases and sepsis.