Abstract
Sphingosine-1-phosphate (S1P) is a potent lipid signaling molecule that regulates pleiotropic biological functions including cell migration, survival, angiogenesis, immune cell trafficking, inflammation, and carcinogenesis. It acts as a ligand for a family of cell surface receptors. S1P concentrations are high in blood and lymph but low in tissues, especially the thymus and lymphoid organs. S1P chemotactic gradients are essential for lymphocyte egress and other aspects of physiological cell trafficking. S1P is irreversibly degraded by S1P lyase (SPL). SPL regulates lymphocyte trafficking, inflammation and other physiological and pathological processes. For example, SPL located in thymic dendritic cells acts as a metabolic gatekeeper that controls the normal egress of mature T lymphocytes from the thymus into the circulation, whereas SPL deficiency in gut epithelial cells promotes colitis and colitis-associated carcinogenesis (CAC). Recently, we identified a complex syndrome comprised of nephrosis, adrenal insufficiency, and immunological defects caused by inherited mutations in human SGPL1, the gene encoding SPL. In the present article, we review current evidence supporting the role of SPL in thymic egress, inflammation, and cancer. Lastly, we summarize recent progress in understanding other SPL functions, its role in inherited disease, and SPL targeting for therapeutic purposes.
Highlights
Sphingosine-1-phosphate (S1P) is a sphingolipid metabolite and a potent signaling molecule that regulates diverse cellular functions such as cell proliferation, differentiation, and migration as well as complex processes including development, vascular maturation, angiogenesis, immune function, and inflammation [1,2,3]
We have further shown that S1P activates quiescent satellite cells (SC) via an S1PR2/ signal transducer and activator of transcription 3 (STAT3)/Rac1-dependent pathway, thereby facilitating skeletal muscle regeneration [13]
S1P lyase (SPL) is a ubiquitously expressed enzyme that is essential for maintaining S1P chemotactic gradients that enable T cell egress and other aspects of hematopoietic cell trafficking
Summary
Sphingosine-1-phosphate (S1P) is a sphingolipid metabolite and a potent signaling molecule that regulates diverse cellular functions such as cell proliferation, differentiation, and migration as well as complex processes including development, vascular maturation, angiogenesis, immune function, and inflammation [1,2,3]. Central and peripheral nervous system functions, inflammation, and carcinogenesis (Figure 1(a)) [9,10,11,12,13,14,15,16,17,18,19,20,21] The majority of these effects can be attributed to the ability of SPL to regulate S1P receptor signaling. The immunological role of S1P/S1PR1, and its regulation of T cell egress from the thymus and lymphoid organs, is the most well-characterized function of the S1P signaling pathway. We discuss progress in the development of SPL inhibitors and their potential therapeutic applications
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