Sphingosine-1-Phosphate and Its Signaling Pathway Modulators: History
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Gary Álvarez Bravo
,
René Robles Cedeño
,
Marc Puig Casadevall
,
Lluís Ramió-Torrentà

Sphingosine-1-phosphate (S1P) and S1P receptors (S1PR) are bioactive lipid molecules that are ubiquitously expressed in the human body and play an important role in the immune system. 

  • S1P
  • S1PR1

1. Introduction

Sphingosine-1-phosphate (S1P) and S1P receptors (S1PR) are bioactive lipid molecules that are ubiquitously expressed in the human body and play a fundamental role in the trafficking and activation in the immune system. The first description by Spiegel et al. defined S1P as a signaling molecule that stimulates fibroblast proliferation [1][2]. S1P itself is a physiologic signaling molecule that acts as a ligand for a group of cell surface receptors. There are five different high-affinity cell surface receptors of S1P, which belong to the superfamily of G protein-coupled receptors (GPCR) [3]. Interaction with specific intracellular targets facilitates the propagation of S1P signals and subsequently, upon release, ligation of the five known heptameric GPCR can result both in autocrine and paracrine signaling [4].
The important role played by S1P/S1PR in various cellular functions such as vascular tone, heart rate, preservation of endothelial barrier and fundamentally, in immune cell trafficking have been proven in multiple studies [5]. This wide range of biological functions leads S1P/S1PR to be involved in pathogenesis of immunological and non-immunological conditions. Thus, S1P and S1PR were proposed as therapeutic targets for prevention or treatment of some diseases [6].

2. Mechanism of Action of S1P/S1PR

The cell membrane is composed of a large number of proteins, among them sphingosines, which in turn are the source of many bioactive lipids, including ceramide, sphingosine, S1P and ceramide-1-phosphate [7][8]. S1P is the active terminal derivative of sphingosine metabolism, generated by the action of sphingosine kinase (SKs) [9][10]. SKs are activated by cytokines, immunoglobulins, hormones, and trophic factors [10]. S1P/S1PR complex has a broad range of functions due to the autocrine and paracrine effects and its presence in the blood and the lymphatic system (Figure 1).
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Figure 1. Schematic summary of the current view of S1PR modulators and S1P signaling pathways with cellular therapeutic targets in inflammation and immune processes through different G proteins.
S1P exerts its action through multiple enzymatic reactions in different cell locations, such as endoplasmic reticulum, mitochondria and nucleus [11][12].
The main S1P effect is regulating the lymphocyte egress from secondary lymphatic organs (SLO) into the systemic circulation, being the SLO the main location where its cardinal function is implemented [13][14][15]. To reach an adequate gradient of lymphocytes between blood and the lymph nodes a perfect equilibrium between the synthesis and degradation of S1P is necessary, via sphingosine kinases and sphingosine lyases, respectively. This equilibrium is altered when a modulator such as fingolimod is introduced [16][17].
S1P was initially thought not to have an active function, but this misconception changed when the S1PR was discovered and its characteristics as first messenger were better understood [18][19]. It has been proven that S1P is involved in multiple biological effects due to both its ubiquitous distribution and its pleiotropic effect, not only in the immune system, but also in limb development, neurogenesis, cardiogenesis, and generation and proliferation of vessels [20][21].
As was previously mentioned, S1P functions are mediated by five GPCR expressed in many organs (S1PR1 to S1PR5) [22]. S1PR1 expressed on lymphocytes T and B is implicated in modulating the expression of some pro-inflammatory cytokines [23][24][25]. S1P is involved in mechanisms of immune tolerance and prevention of autoimmunity. There are some ongoing trials about its implication on autoimmune diseases based on these effects [25][26].
S1P is released by cerebral sphingosines in the central nervous system (CNS), and its receptor is expressed by all types of brain cells, including neurons, astrocytes, and oligodendrocytes [27][28]. The discovery of the presence of the S1P/S1PR complex in the CNS was the main factor to figure out that the modulation of the signaling of this complex might have therapeutic implications for neurological disorders, including multiple sclerosis [29][30].
Given all the previously exposed, the effects of S1P can be theoretically divided into both peripheral effect due to the actions exerted on the immune system, and central effect because of its interactions in the central nervous system [31].

3. S1PR Isoforms

3.1. Sphingosine-1-Phosphate Receptor: Isoform 1 (S1PR1)

S1PR1 is ubiquitous and is virtually expressed in every cell line [32]. Its wide distribution is the reason it has multiple biological effects in various organs [32][33]. As outlined above, S1PR-1 has a peripheral effect in the immune system and other organs and a central effect in the CNS [32]. Multiple functions such as actin remodeling, chemotaxis, lymphocyte egress, vascular integrity, organogenesis including angiogenesis, cell growth and proliferation and antimicrobial cytotoxicity are carried out by immune and vascular cells at peripheral level [33][34] (Figure 2). In CNS, S1PR1 is expressed by astrocytes, microglia, oligodendrocytes and neurons [33]. Its effects vary depending on the cellular lineage, not being well understood yet. Nevertheless, it is thought that S1PR1 induces overexpression of glial fibrillary acidic protein (GFAP) levels and morphological changes in neurons, therefore being directly involved in astrocyte proliferation and activation [35]. In neurons, S1PR1 also stimulates the migration of neuronal progenitor cells towards lesion sites [36]. The S1PR1 effects on oligodendrocyte progenitor cells (OPCs) are not properly stablished, but modulators such as fingolimod or siponimod have failed to show remyelination [34].
Cells 11 02058 g002
Figure 2. S1P receptors and their main localizations altogether with the S1P modulators and their targets. S1PR = Sphingosine1-phosphate receptor, CNS = central nervous system.
The fingolimod causes down-regulation in multiple lines of cells, so immunosuppressive effect is due to the downregulation of S1PR1 on T cells whereas its action on endothelial cells is responsible for increasing permeability and vascular leakage with the subsequent side effects observed after long-term treatment [36].
S1P1 seems to be a promising pharmacological target that remained to be explored in the different diseases in which it is pathophysiological involved.

3.2. Sphingosine-1-Phosphate Receptor: Isoform 2 (S1PR2)

The S1PR2 binds to S1P with high affinity [37]. S1PR2, as well as other S1PR, signals through various G proteins and is widely expressed in different organs [38]. It is supposed that S1PR2 plays an important role in inhibition of apoptosis, cellular proliferation, actin remodeling and B cells positioning in follicles and in the the development of the heart and the auditory and vestibular system [39][40]. The establishing of endothelial barriers, especially in inner ear and retina are other of its key functions [39]. Nonetheless, these biological effects are poorly understood, thus the development of selective modulators has not been studied sufficiently [40][41].

3.3. Sphingosine-1-Phosphate Receptor: Isoform 3 (S1PR3)

The functions of S1PR3 are still not completely clarified, but an essential role in the regulation of vascular tone by mean of vasodilation has been proposed. It is also involved in cytokine production, in the protection of myocardial ischemia, and in coagulation during inflammatory processes [42] (Figure 2). Moreover, S1PR3 enhances the Notch signaling pathway and is implicated in retinal astrogliosis. The S1PR3 effect on immune system remains controversial as both pro-inflammatory and anti-inflammatory effects have been shown [42][43]. Most of the research performed on S1PR3 is related to vascular contraction, stroke, sepsis, cardiac conductivity, asthma and cancer growth and metastasis formation [44][45].
The fingolimod effect on S1PR3 in the heart conduction system causes a negative chronotropic response [46].

3.4. Sphingosine-1-Phosphate Receptor: Isoform 4 (S1PR4)

The S1PR4 is specifically expressed in SLO, hematopoietic tissue and lungs, where it plays an essential role in lymphocyte signaling, megakaryocyte differentiation and platelet formation and activation [47][48] (Figure 2). In CNS, S1PR4 mediates the activation and maturation of dendritic cells [47]. S1PR4 is a negative regulator of cells proliferation and participates in reducing the secretion of effector cytokines [48]. The functioning of S1PR4 system is currently under investigation, and some novel selective agonists are being studied to better understand its biological importance [49].

3.5. Sphingosine-1-Phosphate Receptor: Isoform 5 (S1PR5)

Oligodendrocytes and myelinating cells of the brain and spleen are the cellular lines, which most widely express this S1PR isoform [50]. S1PR5 is one of the main regulators of natural killer cells egress from both bone marrow and spleen into the blood [51]. Activation of the S1PR5 on oligodendrocytes may have a beneficial effect in MS by protecting the oligodendrocytes from demyelination and cell death [52] (Figure 2). Immune quiescence and blood–brain-barrier integrity are other functions that could be mediated by the expression of S1PR5 in the brain endothelial cells [50][51].

This entry is adapted from the peer-reviewed paper 10.3390/cells11132058

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