The S1P-S1PR Axis in Neurological Disorders-Insights into Current and Future Therapeutic Perspectives

Abstract

Sphingosine 1-phosphate (S1P), derived from membrane sphingolipids, is a pleiotropic bioactive lipid mediator capable of evoking complex immune phenomena. Studies have highlighted its importance regarding intracellular signaling cascades as well as membrane-bound S1P receptor (S1PR) engagement in various clinical conditions. In neurological disorders, the S1P-S1PR axis is acknowledged in neurodegenerative, neuroinflammatory, and cerebrovascular disorders. Modulators of S1P signaling have enabled an immense insight into fundamental pathological pathways, which were pivotal in identifying and improving the treatment of human diseases. However, its intricate molecular signaling pathways initiated upon receptor ligation are still poorly elucidated. In this review, the authors highlight the current evidence for S1P signaling in neurodegenerative and neuroinflammatory disorders as well as stroke and present an array of drugs targeting the S1P signaling pathway, which are being tested in clinical trials. Further insights on how the S1P-S1PR axis orchestrates disease initiation, progression, and recovery may hold a remarkable potential regarding therapeutic options in these neurological disorders.

Keywords: S1P1–5; fingolimod; multiple sclerosis; neurodegeneration; sphingosine 1-phoshate; sphingosine 1-phosphate antagonistst/inhibitors; sphingosine 1-phosphate metabolism; sphingosine 1-phosphate receptor; sphingosine 1-phosphate signaling; stroke.

Figure 1

Sphingolipid biosynthesis, sphingosine 1-phosphate (S1P) release, and signaling. S1P is generated in different compartments within a cell. Nuclear S1P influences the balance between chromosome density by histones and telomere length impacting on metabolic adaptations and cell proliferation. De novo S1P synthesized at the smooth endoplasmic reticulum may be utilized for complex sphingolipid synthesis, crucial components of cellular membranes. Mitochondrial S1P influences mitochondrial respiration by activating complex IV. S1P generated at the intracellular leaflet of the plasma membrane (PM) is either used for intracellular signaling converging on the TNFα or the PPARγ pathways or is exported to induce autocrine or paracrine stimulation transported by apolipoprotein (ApoM)-containing high-density lipoprotein (HDL) or albumin and signaling via membrane-bound S1P receptor (S1PR). Intracellularly, S1PR recruit different heterotrimeric G proteins to initiate different signaling pathways, which results in the down-regulation of S1PR via β-arrestin dependent recruitment of G protein receptor β-arrestin-regulated kinase 2 (GRK2), allowing dynamin and moesin-dependent endosome recruitment. Endosomal S1PR are either recruited to the PM or polyubiquitinylated by NEDD4-like E3 ubiquitin ligase WWP2 (WWP2) targeting S1PR for proteasomal degradation. Endosomal remnants are fused with the lysosome (the place where complex sphingolipids are degraded) to fully degrade proteinaceous or lipid cargo, ultimately replenishing the S1P pool. The figure is a modified version of Cartier and Hla [26] and Kunkel et al., [23].

Figure 2

Sphingosine 1-phosphate receptors, canonical pathways, and functions triggered. The currently discovered S1P receptors 1–5 (S1P_1–5) are displayed. S1PR are naturally activated by S1P and to some extent by dihydro-S1P (sphinganine 1-phosphate) and phyto-S1P (4-hydroxysphinganine 1-phosphate), but also competitive/allosteric activation and inhibition by other molecules are described. Upon activation, S1PR can recruit various heterotrimeric G proteins, which, in turn, allow a finely tuned intracellular signaling cascade to be evoked by means of both Gα and Gβγ. Thus, differential S1PR expression in response to varying environmental lipid contexts, i.e., S1P, dihydro-S1P, and phyto-S1P, respectively, may result in a context- and cell type-dependent function triggered.

Figure 3

Clinical significance of distorted sphingosine 1-phosphate signaling in neurological disorders. Perturbed S1P signaling has been reported in various clinical conditions ranging from autoimmunity, infection, and cancer. S1P signaling was also shown to play a detrimental role in several neurological diseases, including neurodegenerative and neuroinflammatory conditions, but equally in cerebrovascular insults resulting in stroke or subarachnoid hemorrhage. The yellow patches refer to demyelinated/inflamed areas in the white matter. The area of the grey matter (grey) highlighted in blue denotes the infarcted region. This region is perfused by the middle cerebral artery (here blocked by an embolus), a branch of the cerebral vessel system (red).