Sphingosine-1-Phosphate Receptor-2 Antagonists: Therapeutic Potential and Potential Risks

Abstract

The sphingosine-1-phosphate (S1P) signaling system with its specific G-protein-coupled S1P receptors, the enzymes of S1P metabolism and the S1P transporters, offers a multitude of promising targets for drug development. Until today, drug development in this area has nearly exclusively focused on (functional) antagonists at the S1P1 receptor, which cause a unique phenotype of immunomodulation. Accordingly, the first-in class S1P1 receptor modulator, fingolimod, has been approved for the treatment of relapsing-remitting multiple sclerosis, and novel S1P1 receptor (functional) antagonists are being developed for autoimmune and inflammatory diseases such as psoriasis, inflammatory bowel disease, lupus erythematodes, or polymyositis. Besides the S1P1 receptor, also S1P2 and S1P3 are widely expressed and regulate many diverse functions throughout the body. The S1P2 receptor, in particular, often exerts cellular functions which are opposed to the functions of the S1P1 receptor. As a consequence, antagonists at the S1P2 receptor have the potential to be useful in a contrasting context and different areas of indication compared to S1P1 antagonists. The present review will focus on the therapeutic potential of S1P2 receptor antagonists and discuss their opportunities as well as their potential risks. Open questions and areas which require further investigations will be emphasized in particular.

LPS and palmitate synergistically stimulate sphingosine kinase 1 and increase sphingosine 1 phosphate in RAW264.7 macrophages

“…A recent study has shown that the S1PR1‐binding molecule FTY720 inhibits osteoclast formation in rats with ligature‐induced periodontitis . In contrast, S1PR2 was found to often exert cellular functions that are opposed to the functions of S1PR1 . To understand why S1PR1 and S1PR2 have different biological functions, studies have shown that S1PR1 and S1PR2 mainly couple to Gi and G12/13, respectively .…”

“…43 In contrast, S1PR2 was found to often exert cellular functions that are opposed to the functions of S1PR1. 44 To understand why S1PR1 and S1PR2 have different biological functions, studies have shown that S1PR1 and S1PR2 mainly couple to Gi and G12/13, respectively. 45 However, it has been also shown that, in addition to G12/13, S1PR2 couples to other G-proteins as well, leading to activation of multiple downstream signaling pathways including mitogen-activated protein kinase and nuclear factor kappa B cascades, which are critically involved in proinflammatory gene expression.…”

Sphingolipids in neutrophil function and inflammatory responses: Mechanisms and implications for intestinal immunity and inflammation in ulcerative colitis

“…FTY720 is a sphingosine analogue that alters lymphocyte trafficking by sequestering cells in secondary lymphoid organs preventing their migration towards sites of inflammation and delaying their return to the circulation. Upon phosphorylation by sphingosine kinase 2 (SK2), FTY720-phosphate functions as an agonist and modulator of G-protein coupled S1PRs, primarily S1PR1 in lymphocytes (Blankenbach et al, 2016). Modulators of S1PR signaling can have implication for diseases characterized by excessive lymphocyte recruitment such as inflammatory bowel disease (IBD) (Izzo et al, 2016; Rivera-Nieves, 2015).…”

Vascular modulation through exercise improves chemotherapy efficacy in Ewing sarcoma

“…S1PR1 expression suppresses hyperpermeability through the stabilization of vascular endothelial cadherin at adherens junctions in response to laminar flow . S1PR2 expression, which is associated with pathologic endothelium and increased vascular permeability, is upregulated by disturbed blood flow, such as that found in tumors . Exercise has been demonstrated to increase S1P ligand expression in the serum of human subjects, but regulation of the receptors in response to exercise has not been evaluated.…”

“…11,13 S1PR2 expression, which is associated with pathologic endothelium and increased vascular permeability, is upregulated by disturbed blood flow, such as that found in tumors. 12,16 Exercise has been demonstrated to increase S1P ligand expression in the serum of human subjects, 17 but regulation of the receptors in response to exercise has not been evaluated. We hypothesized that regulation of S1PR1 and S1PR2 correlates with tumor vascular remodeling in response to exercise-induced shear stress.…”