Sphingosine 1-phosphate Receptor Modulator Therapy for Multiple Sclerosis: Differential Downstream Receptor Signalling and Clinical Profile Effects

Abstract

Lysophospholipids are a class of bioactive lipid molecules that produce their effects through various G protein-coupled receptors (GPCRs). Sphingosine 1-phosphate (S1P) is perhaps the most studied lysophospholipid and has a role in a wide range of physiological and pathophysiological events, via signalling through five distinct GPCR subtypes, S1PR₁ to S1PR₅. Previous and continuing investigation of the S1P pathway has led to the approval of three S1PR modulators, fingolimod, siponimod and ozanimod, as medicines for patients with multiple sclerosis (MS), as well as the identification of new S1PR modulators currently in clinical development, including ponesimod and etrasimod. S1PR modulators have complex effects on S1PRs, in some cases acting both as traditional agonists as well as agonists that produce functional antagonism. S1PR subtype specificity influences their downstream effects, including aspects of their benefit:risk profile. Some S1PR modulators are prodrugs, which require metabolic modification such as phosphorylation via sphingosine kinases, resulting in different pharmacokinetics and bioavailability, contrasting with others that are direct modulators of the receptors. The complex interplay of these characteristics dictates the clinical profile of S1PR modulators. This review focuses on the S1P pathway, the characteristics and S1PR binding profiles of S1PR modulators, the mechanisms of action of S1PR modulators with regard to immune cell trafficking and neuroprotection in MS, together with a summary of the clinical effectiveness of the S1PR modulators that are approved or in late-stage development for patients with MS. Sphingosine 1-phosphate receptor modulator therapy for multiple sclerosis: differential downstream receptor signalling and clinical profile effects (MP4 65540 kb).

Fig. 1

Lysophospholipid receptors and their downstream intracellular signalling pathways. Lysophospholipid ligands (S1P, LPA, LPI and LysoPS) bind to their cognate GPCRs, which activate heterotrimeric G-proteins (defined here by their α subunits) to initiate downstream signalling cascades. The five S1PRs are highlighted in coloured text. Major signalling pathways activated through G_i/o, G_q, G_12/13 and G_s proteins are shown. Signalling through G_i/o can promote: (1) activation of the small GTPase Ras and the ERK to promote proliferation; (2) activation of PI3K and PKB/Akt to increase survival and to prevent apoptosis with important implications for neuroprotection; (3) induction of PI3K and the small GTPase Rac to promote migration, to enhance endothelial barrier function and to induce vasodilation; and (4) activation of PKC and PLC to increase intracellular free calcium (Ca²⁺), which is required for many cellular responses. Furthermore, signalling through G_i/o can inhibit AC activity to reduce cAMP. Signalling through G_q primarily activates PLC pathways and signalling through G_12/13 can promote activation of the small GTPase Rho and the ROCK to inhibit migration, to reduce endothelial barrier function and to induce vasoconstriction. S1PR signalling does not appear to be transduced via G_s. Figure elements reproduced/adapted with permission [15, 55]. AC adenylyl cyclase, ATP adenosine triphosphate, cAMP cyclic adenosine monophosphate, DAG diacylglycerol, EPAC exchange protein activated by cAMP, ERK extracellular signal-regulated kinase, GPCRs G-protein coupled receptors, GTPase guanosine triphosphatase, IP₃ inositol tri-phosphate, LPA lysophosphatidic acid, LPI lysophosphatidyl inositol, LysoPS lysophosphatidyl serine, MAPK mitogen-activated protein kinase, PI3K phosphatidylinositol 3-kinase, PIP phopsatydlinositol phosphate, PKA protein kinase A, PLC phospholipase C, PKB/Akt protein kinase B, PKC protein kinase C, ROCK Rho-associated kinase, S1P sphingosine 1-phosphate, S1PRs sphingosine 1-phosphate receptors

Fig. 2

Interaction of S1PR modulators with S1PR subtypes, downstream Gα subunit targets and their physiological consequences. S1PR modulators are agonists of S1PR₁ and produce functional antagonism. Therefore, the net effect of treatment would be to depress signalling through these pathways. In contrast, S1PR modulators appear to act as traditional agonists of S1PR₅; the expected outcome of treatment would therefore be increased activity through these pathways, although forms of antagonism may occur. Crosstalk between S1PRs and downstream G-protein signalling occurs, with some (but not all) crosstalk depicted (coloured arrows); potential crosstalk through G_q and resulting downstream calcium signalling may have neuroprotective effects. It is important to note that the different pathways are subject to regulation by other activation and differentiation signals that may also affect the relative expression of individual S1PR subtypes on individual cells. Figure elements reproduced/adapted with permission [15, 55]. ^aRequires phosphorylation in situ for activity. CV cardiovascular, S1P sphingosine 1-phosphate, S1PR sphingosine 1-phosphate receptor, T_H17 T-helper cell

Fig. 3

Phylogenetic relationships between S1PRs and other LP receptor family members. Phylogenetic tree of human G-protein coupled receptors and LP receptors. GPCR G-protein coupled receptor, LP lysophospholipid, LPA lysophosphatidic acid receptor, LPI lysophosphatidyl inositol receptor, LyPS lysophosphatidyl serine receptor, S1P sphingosine 1-phosphate receptor. Reproduced/adapted with permission from Chun [15]

Fig. 4

Peripheral and CNS mechanisms of action of S1PR modulators. a Binding of S1PR modulators to S1PR₁ on central memory and naïve T cells produces S1PR₁ internalisation, resulting in cells that are unresponsive to S1PR₁-mediated signalling. Any new S1PR₁ being produced inside the cell will also be functionally antagonised until S1PR₁ modulation is removed. Therefore, activated central memory/naïve T cells do not leave the lymph node in response to S1P signals. By inhibiting their movement into the circulation, S1PR modulator treatment prevents these autoreactive cells from migrating into the CNS. In contrast, the levels of peripheral effector memory T cells are largely unaffected by S1PR modulators, thus preserving immunosurveillance and the capacity to respond to and contain locally invading pathogens. b S1PR modulators can also cross the blood–brain barrier (to varying degrees) and have direct effects on the S1PR subtypes expressed throughout the CNS. c Distribution, signalling and downstream biological effects of targeting S1PR subtypes in CNS cells. Information is from a composite review of the literature covering many different growth conditions in culture, developmental stages, disease states or animal models [49]. CNS central nervous system, OPC oligodendrocyte precursor cell, S1P sphingosine 1-phosphate, S1PR sphingosine 1-phosphate receptor