Sphingosine 1-phosphate: Lipid signaling in pathology and therapy

Abstract

Sphingosine 1-phosphate (S1P), a metabolic product of cell membrane sphingolipids, is bound to extracellular chaperones, is enriched in circulatory fluids, and binds to G protein-coupled S1P receptors (S1PRs) to regulate embryonic development, postnatal organ function, and disease. S1PRs regulate essential processes such as adaptive immune cell trafficking, vascular development, and homeostasis. Moreover, S1PR signaling is a driver of multiple diseases. The past decade has witnessed an exponential growth in this field, in part because of multidisciplinary research focused on this lipid mediator and the application of S1PR-targeted drugs in clinical medicine. This has revealed fundamental principles of lysophospholipid mediator signaling that not only clarify the complex and wide ranging actions of S1P but also guide the development of therapeutics and translational directions in immunological, cardiovascular, neurological, inflammatory, and fibrotic diseases.

Figure 1.. Establishing and maintaining S1P gradients in vessels

S1P is transported by chaperones- ApoM⁺HDL and albumin in the circulation and presented to S1PRs. S1P export by vascular endothelial cells (VECs) and lymphatic endothelial cells (LECs) (by SPNS2) and by RBCs (by MFS2B), as well as degradation of S1P by the phosphatase LPP3 modify the extracellular S1P gradient. Low interstitial tissue S1P is achieved by the S1P lyase. Tissue concentrations of S1P are indicated in parentheses. S1PR: sphingosine 1-phosphare receptor, SPNS2: Sphingolipid Transporter 2, MFSD2B: Major Facilitator Superfamily Domain Containing 2B, LPP3: Lipid phosphate phosphatase 3

Figure 2.. S1PR1 Signaling Regulation

Schematic representation of regulators of S1P receptor-1 (S1PR1) cell surface expression, signaling and turnover. Albumin-S1P, HDL-S1P and FTY720-P activate S1PR1. Internalization of S1PR1 eventually leads to proteasomal degradation by the ubiquitin ligase WW Domain Containing E3 Ubiquitin Protein Ligase 2 (WWP2). CD44 and activated protein C (APC)/ endothelial protein C receptor (EPCR) transactivate S1PR1, while CD69 binds to and downregulates S1PR1 at the cell surface. Endocytosis of S1PR1 is achieved via GPCR kinase 2 (GRK2)-dependent phosphorylation, and endocytic regulators (dynamin, moesin, β-arrestin and AP2/Clathrin). The intracellular signaling of S1PR1 is transmitted via the hetero-trimeric Gαi family proteins, the inhibition of adenylyl cyclase and activation of PI3K-AKT and ERK pathways. Palmitoylation by DHHC5 affects the coupling of S1PR1 to Gαi, while α-synuclein modulates the coupling of S1PR1 with Gαi by removing S1PR1 from lipid rafts. Regulators of other S1PRs are not well characterized.

Figure 3.. S1P function in vascular development, homeostasis and pathology

Vascular network development, maturation and stabilization is regulated by endothelial S1PR1. Activation of S1PR1 inhibits sprouting angiogenesis and vascular endothelial growth factor receptor 2 (VEGRF2), and promotes vascular stability via adherens junctions and cell-extracellular matrix adhesion (integrins). Loss of cell surface S1PR1 and destabilization of the endothelium causes the leakage of plasma and immune cells into the tissue, leading to inflammation. Vascular damage also leads to thrombosis (platelet aggregation) and fibrin deposition in the interstitial space, which activates fibroblasts and macrophages. Loss of S1PR1 signaling on endothelial cells and activated S1PR2 and S1PR3 signaling on macrophages and fibroblasts ultimately leads to tissue fibrosis, with extracellular matrix deposition, and organ dysfunction.

Figure 4.. S1P function in immunity

Immune cell function, egress and survival are highly dependent on the regulation of S1P and S1PR signaling. Innate immune cell localization to inflammatory sites, egress of B and T cells from bone marrow and thymus, towards and out of secondary lymphoid organ marginal zones rely on S1PR cell surface expression and S1P gradient. The metabolism of T cell ATP, as well as the regulation of fate switching between TH17 and regulatory T cells are also S1PR1-dependent. The confinement of activated CD4⁺ T cells in germinal centers within secondary lymphoid organs and spleen is regulated by S1PR2, while SPNS2 and S1PR1 are shown to be implicated in the recruitment of effector T cells to the tumor microenvironment and suppression of metastasis.

Figure 5.. S1P in the central nervous system

S1PRs are important for normal CNS development, neural stem cell self-renewal and differentiation, as well as neural tube closure and the formation of the neurovascular unit (NVU). Dysregulation of S1PRs is also implicated in stroke, subarachnoid hemorrhage (SAH), multiple sclerosis and neurodegenerative diseases, such as Parkinson’s disease (PD), Alzheimer’s disease (AD) and Huntington’s disease (HD).

Figure 0.. S1PR signaling regulates multiorgan pathophysiological processes.

Extracellular S1P gradients created by transporters, chaperones (ApoM⁺HDL) and metabolic enzymes (LPP3) interact with S1PRs on the cell surface. Receptor activity, transmitted via G proteins, is regulated by multiple mechanisms including β-arrestin coupling, endocytosis and receptor modulators. The resultant cellular changes influence multiple organ systems in physiology and disease.