Sphingosine-1-phosphate and immune regulation: trafficking and beyond

Abstract

Sphingosine-1-phosphate (S1P) is a bioactive lipid with important functions in the immune system. S1P levels are regulated by the balance between its synthesis through sphingosine kinases and its degradation by S1P lyase. S1P signals through plasma membrane G-protein-coupled receptors (S1PR1-S1PR5) or acts directly on intracellular targets. Although it has long been known that the S1P-S1PR1 axis mediates T cell egress from lymphoid organs, recent studies have revealed intrinsic functions of S1P and its receptors in both innate and adaptive immune systems that are independent of immune cell trafficking. Here I summarize recent advances in understanding of the roles of S1P and S1P receptors in inflammatory and allergic responses and lymphocyte differentiation, which directly contribute to the regulation of inflammatory and autoimmune diseases. I also describe strategies to target S1P and S1P receptors for immune-mediated diseases, particularly the immunosuppressant FTY720 (fingolimod), which has recently become the first oral therapy for relapsing multiple sclerosis.

Figure 1. S1P synthesis and degradation

S1P is synthesized by the phosphorylation of the precursor sphingosine (Sph) mediated by sphingosine kinases (SphKs). S1P is irreversibly degraded by S1P lyase or dephosphorylated by S1P phosphatases. S1P regulates immune responses by signaling through plasma membrane G protein-coupled receptors (S1P₁–S1P₅) or acting on intracellular targets such as TRAF2. Cer, ceramide.

Figure 2. Function of SphK1 and S1P in innate immune receptor signaling

Engagement of TLR, TNFR and PAR1 results in the activation of SphK1, which catalyzes the formation of S1P from the precursor sphingosine (Sph). Once formed, S1P can bind and activate intracellular targets such as TRAF2. Alternatively, S1P can be secreted outside of the cells via transporter proteins and activate cell surface S1PRs in an autocrine or paracrine manner. The binding partners that link SphK1 to TLR and PAR1 signaling remain unknown (indicated by the blue-colored proteins).

Figure 3. S1P₁ functions in lymphocyte differentiation

(A). Naïve and natural T_reg (nT_reg) cells are generated in the thymus and migrate to peripheral tissues in a S1P₁-dependent manner. Thymic differentiation of nT_reg cells was inhibited by S1P₁. In response to antigen stimulation, naïve T cells can differentiate into iT_reg cells or Th1 that is reciprocally regulated by S1P₁ signaling. (B). Model for S1P–S1P₁-dependent regulation of reciprocal Th1 and iT_reg differentiation. TGF-β treatment induces the expression of SphKs and the initiation of S1P–S1P1–mTOR axis, which feedback inhibits the TGF-β–Smad3 signaling, thereby modulating T cell lineage differentiation.