Sphingosine-1-phosphate Signalling in Aneurysmal Subarachnoid Haemorrhage: Basic Science to Clinical Translation

Abstract

Sphingosine-1-phosphate (S1P) is generated intracellularly and, when transported to the extracellular compartment, predominantly signals through S1P receptors. The S1P signalling pathway has been implicated in the pathophysiology of neurological injury following aneurysmal subarachnoid haemorrhage (aSAH). In this review, we bring together all the available data regarding the role of S1P in neurological injury following aSAH. There is agreement in the literature that S1P increases in the cerebrospinal fluid following aSAH and leads to cerebral artery vasospasm. On the other hand, the role of S1P in the parenchyma is less clear cut, with different studies arguing for beneficial and deleterious effects. A parsimonious interpretation of this apparently conflicting data is presented. We discuss the potential of S1P receptor modulators, in clinical use for multiple sclerosis, to be repurposed for aSAH. Finally, we highlight the gaps in our knowledge of S1P signalling in humans, the clinical challenges of targeting the S1P pathway after aSAH and other research priorities.

Keywords: Outcome; Sphingosine-1-phosphate; Sphingosine-1-phosphate receptor modulators; Subarachnoid haemorrhage.

Fig. 1

Sphingosine-1-phosphate (S1P) signalling pathway. Sphingosine is generated when ceramide is degraded by ceramidase. S1P is synthesised intracellularly via reversible phosphorylation of sphingosine by sphingosine kinase. Intracellularly, S1P can be dephosphorylated back to sphingosine by the action of S1P phosphatase or is degraded to phosphoethanolamine and hexadecanol by the action of S1P lyase. S1P is transported to the extracellular compartment by a number of transporters including ATP-binding cassette (ABC) transporters A1 and C1, MFSD2B and sphingolipid transporter 2 (SPNS2). In the extracellular compartment, S1P can be transported back into cells via the cystic fibrosis transmembrane conductance receptor (CFTR) or signal through S1P receptors (S1PR₁–S1PR₅). In the context of subarachnoid haemorrhage, S1PR signalling influences cell survival, proliferation, inflammation and blood-brain barrier (BBB) integrity and causes cerebral artery vasoconstriction. Created with BioRender.com

Fig. 2

The evidence supporting the action of sphingosine-1-phosphate is fully consistent within the cerebrospinal fluid (CSF) and periarterial spaces (compartment A, pink colour). Though evidence appears to be conflicting within the parenchyma (compartment B, gold colour), there are likely to be reasons for this, as discussed in the text. Created with BioRender.com

Fig. 3

Proposed mechanism by which the rs12949158 single nucleotide polymorphism in the SPNS2 gene may be associated with poor outcome after aneurysmal subarachnoid haemorrhage. A SPNS2 is a sphingosine-1-phosphate (S1P) exporter. Within the SPNS2 gene, the intronic rs12949158 variant (reference allele G) is located within the binding site for the transcription factor ZNF423. B The alternate rs12949158 A allele is associated with significantly increased ZNF423 transcription factor binding affinity. Increased transcription factor binding leads to upregulation of SPNS2, increased S1P export from cells into the cerebrospinal fluid and thereby a higher S1P concentration in the subarachnoid space. S1P binds to S1PR₃ expressed by cerebral artery smooth muscle, leading to worse neurological outcome. Created with BioRender.com

Fig. 4

Proposed rationalisation of evidence regarding the role of sphingosine-1-phosphate (S1P) after aneurysmal subarachnoid haemorrhage. Parenchymal S1P is protective in the initial stages, and this effect is potentiated by the early agonist activity of S1P receptor modulators. In later stages, S1P is deleterious in both cerebrospinal fluid and parenchymal compartments. S1P causes vasoconstriction and, together with other mechanisms, may contribute to vasospasm of large arteries and also possibly of smaller arterioles in both cerebrospinal fluid and parenchymal compartments, respectively, which is delayed in onset. These delayed deleterious effects of S1P can be reversed by S1P receptor modulators, via development of sustained S1P receptor antagonism. Created with BioRender.com