Sphingosine 1-phosphate signaling impacts lymphocyte migration, inflammation and infection

Abstract

Sphingosine 1-phosphate (S1P) is a sphingosine containing lipid intermediate obtained from ceramide. S1P is known to be an important signaling molecule and plays multiple roles in the context of immunity. This lysophospholipid binds and activates G-protein-coupled receptors (GPCRs) known as S1P receptors 1-5 (S1P1-5). Once activated, these GPCRs mediate signaling that can lead to alterations in cell proliferation, survival or migration, and can also have other effects such as promoting angiogenesis. In this review, we will present evidence demonstrating a role for S1P in lymphocyte migration, inflammation and infection, as well as in cancer. The therapeutic potential of targeting S1P receptors, kinases and lyase will also be discussed.

Keywords: FTY720; S1P; lymphocyte trafficking; sphingosine.

Figure 1.

Schematic of S1P signaling. S1P is a blood-borne lipid mediator. It is less abundant in tissue fluids. This results in an S1P gradient, which is important in immune cell trafficking. Most of the biological effects of S1P are mediated by signaling through the cell surface receptors (S1P_1–5), which are coupled to heterotrimeric G proteins and Rac or Rho to control various downstream signaling effectors. In the vascular system, S1P regulates angiogenesis, vascular stability and permeability. In the immune system, it is a major regulator of trafficking of T and B cells. S1P interaction with its receptor is needed for the egress of immune cells from the lymphoid organs (such as thymus and lymph nodes) into the lymphatic vessels. S1P is generated by the conversion of ceramide to sphingosine by the enzyme ceramidase. The subsequent conversion of sphingosine to S1P is catalyzed by SKs 1 and 2. S1P is cleaved irreversibly to hexadecenal and PE, by S1P lyase, which is the degradation pathway.

Figure 2.

Proposed model of IL-6 and S1P crosstalk in hematological malignancies. IL-6 and S1P activate STAT3, leading to expression of Mcl-1. STAT3 upregulates S1P kinase (SK) resulting in increased S1P production.

Figure 3.

The chemical structures of FTY720 phosphate and KRP203. FTY720 phosphate is a well-characterized S1P_1,3–5 agonist and KRP203 is an S1P₁-specific agonist.