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Chemical modulators of sphingosine-1-phosphate receptors as barrier-oriented therapeutic molecules

Key Points

  • Biological barriers regulate the passage of cells, pathogens, fluids, nutrient, ions and signalling molecules between anatomical compartments during homeostasis and disease. The enhancement or protection of the endothelium is desirable in conditions such as acute respiratory distress syndrome or ischaemia–reperfusion injuries, whereas a temporary disruption could facilitate the penetration of drugs across barriers into the central nervous system (CNS). Few of the currently used therapeutics elicit their effects through barrier modulation.

  • The lysophospholipid sphingosine-1-phosphate (S1P) pathway has emerged as a potent modulator of barrier integrity, owing to its ability to modulate a family of high-affinity G protein-coupled receptors, including S1P1, S1P2, S1P3, S1P4 and S1P5.

  • Different subsets of S1P receptors have different and sometimes opposing effects on the regulation of cellular functions. In general, activation of the different S1P receptor subtypes at the surface of endothelial cells favours barrier maintenance under basal conditions, but this equilibrium seems to change in favour of barrier disruption in pathological states.

  • Enhancement of endothelial barrier integrity proceeds by a pathway that involves S1P1 engagement, activation of Rac1, the recruitment of anchoring substrates for polymerized actin, phosphorylated myosin light chain kinase and cortactin, cortical rearrangement of polymerized actin and relocalization of focal adhesions.

  • Synthetic S1P receptor modulators have shown therapeutic efficacy in clinical trials for multiple sclerosis , as well as in a range of animal disease models, including acute respiratory distress syndrome (ARDS), disseminated intravascular coagulation, ischaemia–reperfusion injury, solid graft transplantation and experimental autoimmune encephalomyelitis.

  • Given that S1P2 and S1P3 have opposite effects to S1P1 with regards to the regulation of endothelial barrier permeability, the design of therapeutics targeting S1P signalling for a range of conditions will require further work on genetic models and the development of specific molecular probes directed towards unique receptor subtypes.

Abstract

Biological barriers regulate the passage of cells, pathogens, fluids, nutrients, ions and signalling molecules between anatomical compartments during homeostasis and disease. Yet strategies that allow for reversible therapeutic modulation of these barriers are still in their infancy. The enhancement or protection of natural barriers is desirable in conditions such as acute respiratory distress syndrome or ischaemia–reperfusion injuries, whereas a temporary disruption could facilitate the penetration of drugs across such barriers. This Review discusses the role of sphingosine-1-phosphate receptors in the regulation and protection of biological barriers, and the potential of therapeutic strategies that target this receptor family.

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Figure 1: The sphingosine-1-phosphate (S1P) biosynthetic pathway.
Figure 2: Sphingosine-1-phosphate (S1P) receptor signalling.
Figure 3: Involvement of sphingosine-1-phosphate (S1P) receptors in the regulation of physiological and pathophysiological phenomena.
Figure 4: Effects of sphingosine-1-phosphate (S1P)–S1P receptor 1 (S1P1) tone on the endothelium of blood vessels.
Figure 5: Targets for endothelial barrier protection during inflammation.
Figure 6: Putative strategies for modulating the immune response in the central nervous system (CNS).

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Acknowledgements

Work in the laboratory of H.R. is supported by the National Institutes of Health (AI-055509, MH-074404 and AI-074564) and by Specific Funding Proposal-1599 from Kyorin Pharmaceutical Company D.M. is supported by the Fonds de la Recherche en Santé du Québec. We thank our colleagues for useful discussions.

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Hugh Rosen has received funding from Kyorin Pharmaceuticals

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Marsolais, D., Rosen, H. Chemical modulators of sphingosine-1-phosphate receptors as barrier-oriented therapeutic molecules. Nat Rev Drug Discov 8, 297–307 (2009). https://doi.org/10.1038/nrd2356

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