Targeting the Metabolism and Receptors of Sphingosine-1- Phosphate for the Treatment of Rheumatoid Arthritis

Abstract

Sphingolipids belong to a major class of lipids that are ubiquitously synthesized by eukaryotic cells and are characterized by their sphingoid backbone and primary structural roles in membrane formation. Over the past two decades, sphingolipids have emerged as a source of important signalling molecules in addition to their structural functions (Merrill et al., 1997). In particular, sphingosine-1-phosphate (S1P), is a unique signalling molecule that has the ability to act as an intracellular second messenger, as well as an extracellular stimulus through specific G protein-coupled receptor (GPCRs) (Pyne and Pyne, 2000; Spiegel and Milstien, 2003; Van Brocklyn et al., 1998). S1P has been shown to mediate a variety of fundamental biological processes including cell proliferation, migration, invasion, angiogenesis, vascular maturation and lymphocyte trafficking. The intracellular level of S1P is tightly regulated by the equilibrium between its synthesis by sphingosine kinases (SphKs) and its degradation by S1P phosphatases (SPPs) and S1P lyase (SPL) (Saba and Hla, 2004). Activation of SphKs by a variety of agonists, including growth factors, cytokines and hormones, increases intracellular S1P. Once generated, S1P can either act intracellularly as a second messenger or be secreted out of the cell and act extracellularly by binding to and signalling through S1P receptors expressed on the surface of the same cell or nearby cells in autocrine and/or paracrine manners (Alvarez et al., 2007). Many of the biological effects of S1P are mediated by its binding to and activation of its specific receptors S1P1–S1P5 (Ishii et al., 2004). Alterations in S1P signalling, as well as in the enzymes involved in its synthesis and metabolism, have been observed in many types of pathological situations such as angiogenesis, metastasis, and autoimmunity. The role played by S1P in the autoimmune disease rheumatoid arthritis (RA) has recently emerged. Activated SphK and elevated levels of S1P have been detected in the synovium and synovial fluids of patients with RA, respectively (Kamada et al., 2009; Kitano et al., 2006; Lai et al., 2008). In addition, exogenously applied S1P in cultured synovial fibroblasts from RA patients causes cell migration, production of cytokines/chemokines, expression of cyclooxygenase-2 and prostaglandins, as well as cell proliferation and survival (Kitano et al., 2006; Zhao et al., 2008). These results suggest a biological function for the SphK/S1P/S1P receptor (S1PR) axes in RA disease progression. In this review we summarize the current understanding of how S1P metabolism and signalling impact the biology of inflammation in