Sphingosine 1-phosphate and inflammation

Sphingosine 1-phosphate (S1P), a sphingolipid mediator, regulates various cellular functions via high-affinity G protein-coupled receptors, S1P(1-5). The S1P-S1P receptor signaling system plays important roles in lymphocyte trafficking and maintenance of vascular integrity, thus contributing to the regulation of complex inflammatory processes. S1P is enriched in blood and lymph while maintained low in intracellular or interstitial fluids, creating a steep S1P gradient that is utilized to facilitate efficient egress of lymphocytes from lymphoid organs. Blockage of the S1P-S1P receptor signaling system results in a marked decrease in circulating lymphocytes because of a failure of lymphocyte egress from lymphoid organs. This provides a basis of immunomodulatory drugs targeting S1P(1) receptor such as FTY720, an immunosuppressive drug approved in 2010 as the first oral treatment for relapsing-remitting multiple sclerosis. The S1P-S1P receptor signaling system also plays important roles in maintenance of vascular integrity since it suppresses sprouting angiogenesis and regulates vascular permeability. Dysfunction of the S1P-S1P receptor signaling system results in various vascular defects, such as exaggerated angiogenesis in developing retina and augmented inflammation due to increased permeability. Endothelial-specific deletion of S1P(1) receptor in mice fed high-fat diet leads to increased formation of atherosclerotic lesions. This review highlights the importance of the S1P-S1P receptor signaling system in inflammatory processes. We also describe our recent findings regarding a specific S1P chaperone, apolipoprotein M, that anchors to high-density lipoprotein and contributes to shaping the endothelial-protective and antiinflammatory properties of high-density lipoprotein.