Shaping the landscape: Metabolic regulation of S1P gradients

Abstract

Sphingosine-1-phosphate (S1P) is a lipid that functions as a metabolic intermediate and a cellular signaling molecule. These roles are integrated when compartments with differing extracellular S1P concentrations are formed that serve to regulate functions within the immune and vascular systems, as well as during pathologic conditions. Gradients of S1P concentration are achieved by the organization of cells with specialized expression of S1P metabolic pathways within tissues. S1P concentration gradients underpin the ability of S1P signaling to regulate in vivo physiology. This review will discuss the mechanisms that are necessary for the formation and maintenance of S1P gradients, with the aim of understanding how a simple lipid controls complex physiology.

Sphingosine Kinases Are Not Required for Inflammatory Responses in Macrophages

“…Prior to the cloning and characterization of the G protein-coupled receptors for S1P (39,40), S1P was considered to be a "second messenger" (41)(42)(43), in a fashion analogous to the well characterized intracellular signaling molecules such as diacylglycerol and cAMP. However, it is now clear that many of the biological effects of S1P, for example, regulation of lymphocyte egress, endothelial cell barrier function, angiogenesis, fibroblast proliferation and survival require the action of the G protein-coupled S1P receptors (1,2,44). Indeed, specialized transporters for S1P, such as Spns2, mediate the export of S1P and maintain the vascular S1P gradient in vertebrates (45,46).…”

Sphingosine-1-phosphate Phosphatase 1 Regulates Keratinocyte Differentiation and Epidermal Homeostasis

“…The lack of any other apparent major phenotypic consequences may be due to alternative pathways that serve to maintain low S1P levels in most tissue compartments. A major S1P degradative pathway is via S1P lyase-mediated cleavage, a process that occurs in many cells and tissues (56). S1P lyase-deficient mice exhibit highly elevated S1P levels in circulation and in tissues, along with diverse phenotypic aberrations, notably in the immune system (9, 57), but, interestingly, not the skin phenotype exhibited by the Sgpp1 null mice.…”

Altered distribution and function of natural killer cells in murine and human Niemann-Pick disease type C1

“…The catabolism of ceramide to produce the sphingosine required for the generation of S1P can occur in several cellular compartments and in the extracellular space by the action of multiple pH-sensitive ceramidases. 43 However, because sphingosine kinase is expressed in the cytosol, the majority of S1P is generated intracellularly and requires transport out of the cell to act on extracellular receptors. 43 It has recently been shown that Spns2 is an S1P transporter essential for immune system function and that expression of Spns2 in endothelial cells is required for correct lymphocyte trafficking, 44,45 but the results on the impact on S1P levels in the lymphatic fluid and plasma are conflicting.…”

“…43 However, because sphingosine kinase is expressed in the cytosol, the majority of S1P is generated intracellularly and requires transport out of the cell to act on extracellular receptors. 43 It has recently been shown that Spns2 is an S1P transporter essential for immune system function and that expression of Spns2 in endothelial cells is required for correct lymphocyte trafficking, 44,45 but the results on the impact on S1P levels in the lymphatic fluid and plasma are conflicting. 45,46 Furthermore, these studies indicate that Spns2 can transport sphingosine in addition to S1P, 46 so it could be that the increased sphingosine competes with S1P for transport.…”