The Many Roles of Lysophospholipid Mediators and Japanese Contributions to This Field

Abstract

Lysophospholipids are phospholipids with only one fatty acid. During the past two decades, it has become apparent that lysophospholipids are not merely degradation products but have various physiological and pathological functions in vivo via G protein-coupled receptor (GPCR)-type receptors. These include lysophosphatidic acid (LPA), sphingosine 1-phosphate (S1P), lysophosphatidylinositol/lysophosphatidylglucose (LPI/LPtdGlc), and lysophosphatidylserine (LysoPS). This review focuses on identifying the functions of the receptors, enzymes, transporters, and carrier proteins required for these four lysophospholipids to function as lipid mediators. We also note that many of advances in this field have been made by Japanese pharmaceutical scientists.

1. INTRODUCTION

Phospholipids (PL) in the membrane usually have two fatty acid acyl chains linked to a glycerol backbone, mainly via ester bonds (Fig. 1), which are relatively weak among several chemical bonds present in the cells. In addition, because of the presence of numerous hydrolases that cleave the ester bonds, i.e., phospholipases (phospholipase A₁ (PLA₁), phospholipase A₂ (PLA₂), phospholipase C (PLC), and phospholipase D (PLD)) (Fig. 1), a variety of PL degradation products are constantly generated, especially under pathological conditions. Among the products are lysophospholipids (LPLs). LPLs are PLs with only one acyl chain (Fig. 2). It has long been known that LPLs act on cell membranes and exhibit detergent-like effects that lead to disruption of cell membranes, an activity that is not induced by conventional PLs with two acyl chains. The “lyso” in the word lysophospholipid is derived from “lysis,” indicating hemolysis. Like PLs, LPLs are classified according to their polar heads (Fig. 2). For example, an LPL with choline in the polar head is called lysophosphatidylcholine (LPC or lysoPC), and one with L-serine is called lysophosphatidylserine (LysoPS, LPS or lysoPS) (Fig. 2). In this review, we abbreviate lysophosphatidylserine as LysoPS to avoid confusion with LPS, which we frequently use as an abbreviation for lipopolysaccharide. LPLs are also roughly classified into glycero- and sphingo-LPLs, depending on their chemical structures (Fig. 2). Glycero-LPLs have a glycerol backbone, whereas sphingo-LPLs have a sphingosine backbone in their structures (Fig. 2). Previous studies have shown that some LPLs have pharmacological effects at the cell and animal levels. For example, intravenous (i.v.) injection of LPA in rats induced rapid hypotension followed by transient hypertension.^1,2) LPA also stimulated the survival and proliferation of many cells in culture.³⁾ LysoPS stimulated the degranulation of mast cells.⁴⁾ However, little had been known about the mechanism of action of LPLs. In addition, their presence in vivo, as well as their pathophysiological functions, had long been unknown. This was because, unlike protein-derived signaling molecules, LPLs are not encoded by the genome directly, and identifying the enzymes and receptors for LPLs was critical to uncovering their roles. Over the past two decades, the identification of many enzymes and receptors for LPLs and the rapid accumulation of knowledge on their gene knockout (KO) mice and human diseases have shown that LPLs play several physiological and pathological roles in vivo.^5–9)

Fig. 1. Structure of a Phospholipid Molecule and Chemical Structures on Which Phospholipases Act

Phospholipids have two fatty acids attached to glycerol via ester bonds, a phosphate group attached to glycerol via a phosphodiester bond and hydroxyl group-containing molecules (X) such as choline, serine and inositol attached to the phosphate group by a phosphodiester bond. Ester and phosphodiester bonds are energetically weak and are subjected to hydrolysis by various phospholipases. These phospholipases include PLA₁, PLA₂, PLC and PLD, and the chemical bonds they hydrolyze are indicated by arrows.

Fig. 2. Structure of Various Lysophospholipids

Lysophospholipids are phospholipids with only one fatty acid chain. They are classified into glycerolysophospholipids and sphingolysophospholipids depending on whether they have a glycerol or sphingosine backbone. Glycerolysophospholipids differ in their polar head and are classified as lysophosphatidylcholine (LPC), lysophosphatidylethanolamine (LPE) and lysophosphatidylserine (LysoPS), etc. S1P is a representative sphingolysophospholipids. Platelet-activating factor (PAF) is a unique lipid mediator with LPC like structure.

With only one acyl chain (Fig. 2), LPLs are amphiphilic and less hydrophobic than conventional PLs with two acyl chains, and thus can be easily liberated from the cell membrane. In addition, LPLs are subjected to dephosphorylation and re-acylation reactions which lead to their prompt eliminations. These properties of LPLs, i.e., being produced from PLs that are abundant in the cell membrane, being released from the cell, and being eliminated immediately, are probably major reasons why LPLs have acquired functions as lipid mediators. Interestingly, all vertebrates including fish have multiple G protein-coupled receptors (GPCRs) for LPLs.^10,11) These LPL GPCRs are responsible for most of the pathophysiological functions exhibited by LPLs. As bioactive lipids, prostaglandins, leukotrienes, and steroids have been characterized as first generation lipid signaling molecules and have critical biological roles and serve as drug targets.^12,13) Currently, LPLs are attracting attention for their biological functions and drug discovery applications as second-generation bioactive lipids.

Figure 3 shows the steps involved in the production and action of LPLs. In principle, LPLs are generated by producing enzymes from cell membrane lipid precursors, act on receptor proteins specific to each LPL and exhibit their biological effects mainly through G protein signaling. In many cases, once produced, LPLs are enzymatically degraded rapidly. LPLs are generated both extracellularly and intracellularly. Some LPLs that are produced intracellularly, such as sphingosine 1-phosphate (S1P), are transported extracellularly and delivered to the target cells by transfer or carrier proteins. In this flow, the producing and degrading enzymes, transporters, carrier proteins, and receptors, are all essential for LPL signaling (Fig. 3). Historically, the references cited in this review reflect the many contributions to LPL research made by Japanese pharmaceutical researchers. Their contributions include the identification of roles of key molecules such as LPA, S1P, LysoPS and many of the functions of LPL-related proteins.

Fig. 3. Working Flow of LPL Mediators

Lysophospholipid mediators are produced from lipid precursors by several producing enzymes and are presented to GPCR-type receptors via carrier proteins and transporters. Downstream of the GPCR are four G proteins and their effector molecules, which induce a variety of cellular responses, physiological and pathological functions. Lysophospholipid mediators are also negatively regulated by degradative enzymes.

2. LYSOPHOSPHATIDIC ACID, LPA

2.1. Structure, Distribution, and Pharmacological Actions

LPA is one of the simplest glycerophospholipids in structure, with one acyl chain and a phosphate group attached to the glycerol backbone (Fig. 2). Interestingly, several LPA species differ in the type of fatty acid (e.g., palmitic acid, oleic acid, arachidonic acid, etc.) and the position to which the fatty acid binds. More interestingly, the structural differences significantly affect the ability to activate LPA receptors in a receptor subtype-dependent manner. For example, LPA with an unsaturated fatty acid at the sn-2 position is a potent ligand for LPA₃ and LPA₆ receptors.^14,15)

In 1978, Tokumura et al. at Tokushima University found that LPA caused an increase in blood pressure when administered to rats.²⁾ Tokumura et al. further showed that plasma pre-incubated at 37 °C had a similar hypertensive effect.¹⁶⁾ Interestingly, pre-incubated plasma had no such hypertensive effect, showing that LPA was produced in the incubated plasma. The result also showed that both substrates and enzymes were present in the plasma to produce LPA. This finding later led to the discovery of the plasma LPA-producing enzyme, autotaxin/lysophospholipase D.

Another prominent pharmacological effect of LPA was that LPA stimulated the survival and proliferation of various cell types.³⁾ This effect was observed mainly in fibroblasts, smooth muscle cells, and specific cancer cells. LPA was rarely present in fresh plasma but abundant in serum, with a strong cell proliferative effect. LPA was once considered a significant growth factor in serum, but the prevailing view now is that LPA promotes cell proliferation by inhibiting cell death and promoting cell adhesion and by transactivating growth factor receptors, such as epidermal growth factor (EGF) receptors.^17–19)

2.2. LPA Receptors

The mechanism by which LPA promotes cell proliferation was not understood until recently. In 1989, Moolenaar’s group in the Netherlands showed that the cell proliferation-promoting effect of LPA was inhibited by pertussis toxin (PTX), an inhibitor of the Gαi protein. The result strongly suggested that LPA receptor(s) were Gαi-coupled GPCR.³⁾ In the 1990s, several GPCRs were identified as prostaglandin receptors by Narumiya’s group at Kyoto University.²⁰⁾ In 1991, Shimizu’s group at the University of Tokyo identified a GPCR that specifically responds to platelet-activating factor (PAF) which is structurally very similar to LPLs²¹⁾ (Fig. 2). The discovery of prostaglandins and PAF receptors accelerated the receptor search studies on LPA and S1P. S1P is a structural analog of LPA (Fig. 2). Thus, many researchers believed that S1P shared its receptors with LPA since LPA and S1P showed similar cellular distributions and induced similar cellular responses in G protein-dependent manner.⁹⁾

In 1996, the first GPCR-type LPA receptor was identified by Chun’s group at UCSD (U.S.A.).²²⁾ This receptor, termed vzg-1, or endothelial differentiation gene 2 (Edg2), was a GPCR that is highly expressed in the ventricular zone of the brain during development. This first LPA receptor was called LPA₁ or LPAR1.⁶⁾ In addition, as the human genome project proceeded, eight homologs of Edg2 (Edg1–8) were found in the genome and cDNA databases. This finding triggered a worldwide search for ligands for EDG family members. As a result, by 2000, Edg4 and Edg7 were identified as the second and third LPA receptors, respectively, and Edg1 (S1P₁, S1PR1), Edg3 (S1P₃, S1PR3), Edg5 (S1P₂, S1PR2), Edg6 (S1P₄, S1PR4), and Edg8 (S1P₅, S1PR5) were identified as S1P receptors^6,23) (Fig. 2). Of these, the ligands of Edg7 and Edg5 were identified by our group and Takuwa’s group at the University of Tokyo, respectively.^24,25)

In 2004, Ishii and Shimizu at the University of Tokyo identified an orphan GPCR, P2Y9, as a fourth LPA receptor as a part of their study on an orphan GPCR ligand identification project.²⁶⁾ P2Y9 is a member of the P2Y family, whose members were thought to be receptors for nucleotides such as ATP. This discovery led to the identification of GPR92 and P2Y5, both of which are close homologs of P2Y9, by Chun’s group as a fifth and sixth LPA receptor, respectively.^15,27,28) PSP24, P2Y10, and GPR35 were also proposed as functional LPA receptors, but there have been no follow-up reports on these GPCRs. Currently, a total of six different GPCRs for LPAs have been identified. Multiple GPCRs have been identified for each of histamine and prostaglandin E2, but, interestingly, LPA has the highest number.

2.3. LPA-Producing Enzymes

In contrast to the mechanism of LPA action through LPA receptors, the molecular mechanism of LPA production was poorly understood at the beginning of 2000, when several LPA receptors had been cloned. Several reports had indicated that LPA was produced in multiple pathways both in cells and in biological fluids such as serum and plasma.²⁹⁾ At least two pathways were postulated.³⁰⁾ LPA is mainly converted from lysophosphatidylcholine (LPC) in serum and plasma, which is abundantly present in these biological fluids.²⁹⁾ By contrast, in platelets and some cancer cells, LPA appeared to be produced from phosphatidic acid (PA).^29,31) Both pathways need two phospholipase activities. The first pathway needs phospholipase A₁ (PLA₁)/PLA₂ and lysophospholipase D (lysoPLD) activities, while the second pathway needs phospholipase D (PLD) and PLA₁/PLA₂ activities (Fig. 4). Our and Tokumura’s groups succeeded in purifying a plasma enzyme called autotaxin (ATX) which has lysoPLD activity against LPC and other LPLs.^32,33) Our group also identified membrane-bound phosphatidic acid-selective phospholipase A₁α (mPA-PLA₁α) which produces LPA from PA by its PLA₁ activity specific to PA³⁴⁾ (Fig. 3). In theory, all PLA₁s and PLA₂s are potential candidates for LPA-producing enzymes. However, ATX and mPA-PLA₁α are the only LPA-producing enzymes proven to produce LPA in vivo and functionally supply LPA to LPA receptors.

Fig. 4. Production, Degradation, Transport, and Action of Lysophosphatidic Acid (LPA) and Sphingosine 1-Phosphate (S1P)

Whereas LPA is produced extracellularly, S1P is produced intracellularly. At least two pathways are postulated for LPA. In the autotaxin (ATX) pathway, LPLs, mainly LPC, are produced by the action of PLA1/2, and the resulting LPLs are converted to LPA by ATX. In the mPA-PLA₁α pathway, PA is generated by PLD, and the resulting PA is converted to LPA by mPA-PLA₁α. LPA targets the six LPA receptors (LPAR1–6). S1P is produced mainly from sphingosine (Sph) by SphK1 and SphK2. S1P produced intracellularly is transported outside by S1P-specific transporters (Spns2 and MFSD2B). S1P is degraded by lyase to hexadecenal (HD) and phosphoethanolamine (PE). After transport to the extracellular milieu, S1P binds to ApoM on high-density lipoprotein (HDL) and circulates in the bloodstream. LPPs are also responsible for extracellular degradation of LPA and S1P. HDL-bound S1P is brought close to the receptors (S1PR1–5), which then activates intracellular signaling pathways.

2.4. LPA Degrading Enzymes

In 1992, Kanoh’s group purified and cloned a cDNA for a membrane-bound phosphatase which preferentially dephosphorylated phosphatidic acid (PA) from porcine thymus membranes.³⁵⁾ The enzyme, called PAP2b, was a membrane protein that catalyzes its reaction extracellularly. PAP2b is now known as lipid phosphate phosphatase 3 (LPP3), and dephosphorylates PA, LPA, S1P and ceramide 1-phosphate (C1P) and is known to negatively regulate both LPA and S1P signaling.^35,36) There are three isoforms of LPPs (LPP1-LPP3).³⁷⁾ Recently, Smyth’s group at University of Kentucky (U.S.A.) demonstrated that LPP3 negatively regulates phenotypic modulation of smooth muscle cells after vascular injury by regulating LPA signaling.³⁸⁾ The in vivo roles of the LPP1 and LPP2 remain unclear.

2.5. Biological Roles of LPA via LPA Producing Enzymes and Receptors

After LPA receptors and LPA-producing enzymes were discovered, several pathophysiological roles of LPA have been elucidated through studies using knockout mice and genetic diseases of LPA receptors and producing enzymes. We recently reviewed the physiological and pathological functions of these LPA receptors and LPA-producing enzymes.⁹⁾ They are summarized in Table 1. We briefly review them here.

Table 1. Pathophysiological Functions of LPL Receptors and Producing Enzymes

Receptor
Ligand	Receptor	Other name	G protein coupling	Model/expression site/cell type	Pathophysiological function	Ref.
LPA	LPAR1	LPA1, EDG2, vzg-1	Gαi	Chondrocytes and osteoblasts	Cartilage and bone formation	18,40)
				Ventricular zone in the brain	Development of the brain	41,113)
				Lung fibroblast	Development of fibrosis	42)
				Neuron	Induce neuropathic pain	114,115)
				Carcinoma cell lines	Stimulate cell motility	116)
	LPAR2	LPA2, EDG4	Gαs	Epithelial cells in the small intestine	Protect from cell death induced by DNA damage	44,117)
	LPAR3	LPA3, EDG7	Gαq	Endometrial epithelium of uteri	Regulate embryo implantationDevelopment of endometriosis	46,47)
	LPAR4	LPA4, GPR23, P2Y9	Gα12, Gα13	Blood and lymphatic vessel	Embryonic blood vessel formation	48)
				Adipocytes, diet-induced obesity model	Negative regulation of remodeling and healthy expansion of WATPromote obesity-related metabolic disorders	49)
	LPAR5	LPA5, GPR92, GPR93	Gαi, Gα12, Gα13	T and B lymphocytes	Suppress lymphocyte activation	50,51)
				DRG neurons	Itch sensation	118)
	LPAR6	LPA6, P2Y5	Gα12, Gα13	Keratinocytes in Hair follicle	Hair follicle formationCongenital hairless diseases	19,119)
S1P	S1PR1	EDG1	Gαi	Vascular smooth muscle cells and endothelial cells	Vascular maturation and blood vessel formation	73,74)
				T and B lymphocytes	Regulate egress from lymphoid organs	78)
	S1PR2	EDG5	Gαi, Gα12, Gα13, Gαq	GC B cells	Promote confinement of GC B cell to GC	79)
	S1PR3	EDG3	Gαi, Gα12, Gα13, Gαq	Corneal injury model	Improve management of the corneal wound healing response	120)
				Bleomycin-induced lung injury model	Attenuate pulmonary inflammation and fibrosis	121)
	S1PR4	EDG6	Gαi, Gα12, Gα13	Polyoma middle T (PyMT) tumor model, CD8 T cell	Restrict CD8 T cell expansion	122)
	S1PR5	EDG8	Gαi, Gα12, Gα13	Effector and memory T cell	Control generation of tissue-resident lymphocytes	123)
LPI/LPtdGlc	GPR55	LPIR1	Gα12, Gα13	Neurons (nociceptive afferent axons)	Regulate the targeting of central axon projections during brain development	82)
				Osteoclast	Regulate osteoclast number and function	124)
				Pancreatic β cells	Promote insulin secretion stimulated by glucose	125)
				Salivary glands	Regulate cell proliferation and function	94)
				γδT cell	Suppress T cell homing and accumulation in the small intestine	126)
LysoPS	LPSR1	LPS1, GPR34	Gαi	Fungal infection model	Promote fungal infection defense	108)
				Neuropathic pain model	Enhance microglial pro-inflammatory responses	109)
				DTH model	Regulate pro-inflammatory cytokine production	108)
				Primary microglia	Promote phagocytic activity	127)
				Born marrow dendritic cell	Regulate apoptosis signaling pathway	128)
				Type 3 innate lymphoid cell	Defend against fungi infection and maintain tissue homeostasis	129)
				Cervical, gastric, and colorectal cancer cell	Promote cellular invasion and proliferation	130,131)
	LPSR2	LPS2, P2Y10	Gα12, Gα13	CD4 T cell	Regulate chemokine-induced migration, polarization and RhoA activation	112)
				Primary microglia and dendritic cell	Suppress LPS-induced pro-inflammatory responses	132)
				Primary eosinophil	Promote degranulation, survival, and formation of EET	133)
	LPR2L	LPS2L, A630033H20Rik	Gα12, Gα13	Not determined	Not determined
	LPSR3	LPS3, GPR174	Gαs, Gαi	EAE and septic model	Attenuate disease severity by enhancing anti-inflammatory responses by Treg	134,135)
				Primary CD4 T cell	Suppress IL-2 production	110)
				Splenic follicle B cell in male mice	Regulate the cellular migration into the follicle center and formation of germinal centers	111)
				Splenic marginal zone B cell	Inhibit the inflammatory responses and proliferation	136)
Producing enzyme
Product	Enzyme	Other name		Model/expression site/cell type	Pathophysiological function	Ref.
LPA	Autotaxin	LysoPLD, NPP2		Caudal vein plexus of zebrafish	Embryonic blood vessel formation	60,137)
				High endothelial cells in HEV	Mediate Lymphocyte homing	138,139)
				Neuron	Induce neuropathic pain	140)
				Cancer cell lines	Regulate cancer metastasis	116,141)
				Endometrial epithelium of uteri	Regulate embryo implantation	47)
	mPA-PLA1α	LIPH, LPDLR		Hair follicle	Hair follicle formation	19,142)
S1P	SphK1	SPHK		Macrophage, tumor model	Promote pulmonary metastasis and tumor lymphangiogenesis	143)
	SphK2	SK-2, SPK-2		Macrophage	Promote anti-inflammatory responses	144)
LysoPS	PS-PLA1	PLA1A		Not determined	Accelerate degranulation reactions by mast cell	104)
	ABHD16A	BAT5		Brain	Regulate neuroimmunological disorders	145)

The first impact of the in vivo role of LPA came from phenotypic analysis of LPAR1 KO mice. Lpar1 KO mice have a unique facial appearance, which was later shown to be due to abnormalities in the cartilage tissue present at the base of the skull.^18,39) LPAR1 is predominantly expressed in fibroblasts and their relatives, including chondrocytes and osteoblasts. Consistent with this, Lpar1 KO mice show marked abnormalities in cartilage and bone.^18,40) Another major LPAR1-expressing cell is the neuron, especially in the embryonic stages. Lpar1, also Vzg-1, is highly expressed in the ventricular zone and negatively regulates neural cell death. LPAR2 also has a redundant role since LPA-induced hypertrophy of embryonic mouse brain was not observed in Lpar1/Lpar2 double KO mice.⁴¹⁾ LPAR1 signaling is also pathologically important. Lpar1 KO mice were completely resistant to bleomycin-induced lung fibrosis, which accelerated the development of an LPAR1 antagonist as a potential drug preventing lung fibrosis, especially idiopathic pulmonary fibrosis (IPF).^42,43)

LPAR2 also mediates anti-apoptotic or survival signals, especially in the intestine. Administration of LPA or an LPAR2 agonist efficiently suppressed the cell death of a type of epithelial cell in the small intestine induced by either X-ray irradiation or anti-cancer drugs.^44,45)

LPAR3 is unique in that it mainly mediates Gαq signaling. Lpar3 KO mice are unlikely to become pregnant even when crossed with wild-type males, and even if they become pregnant, the litter size is small. Lpar3 KO interferes with implantation of fertilized eggs, probably because the endometrial epithelium of the uterus, which highly expresses Lpar3 during the implantation period, does not undergo morphological changes to accommodate the fertilized egg.^46,47)

Lpar4 is expressed widely and has various pathophysiological roles. Some but not all Lpar4 KO mice displayed hemorrhages and edema in many organs at multiple embryonic stages.⁴⁸⁾ The recruitment of pericytes was impaired in these abnormal mice, suggesting that LPAR4 regulates blood and lymphatic vessel formation during mouse embryogenesis. LPAR4 also has a role in adipose tissues, where it limits proper adipose tissue expansion and remodeling in diet-induced obesity.⁴⁹⁾

LPAR5 function has been poorly characterized. However, it has been proposed that LPAR5 is expressed on T and B lymphocytes where it negatively regulates lymphocyte activation via T and B cell receptors.^50,51)

LPAR6 has a unique role in hair follicle formation, which was revealed from the studies on congenital hairless diseases in humans.^52,53) Interestingly, PAPLA1 (LIPH), which encodes an LPA-producing enzyme (mPA-PLA₁α), was identified as another causative gene of hair loss diseases in various families around the world. Similar body hair abnormalities due to the missense mutation in the Liph gene were reported in rabbits.⁵⁴⁾ Both Lpar6 and Liph are highly expressed in specific layers of the hair follicle in mice. In addition, the mutant mice have abnormally structured hair follicles.¹⁹⁾ Thus, LPA produced by mPA-PLA₁α acts on LPAR6 in the hair follicle, contributing to proper hair follicle formation.

A completely unexpected role of LPA, a role in angiogenesis, was revealed by an analysis of mice in which the LPA-producing enzyme ATX was knocked out.^55,56) ATX KO mice were found to be embryonic lethal around embryonic day 10.5 due to a defect in blood vessel formation. The LPA receptors downstream of ATX could not be identified because none of the six Lpar KO mice (LPAR1–LPAR6) showed the embryonic lethality and the blood vessel defect. Interestingly, the phenotype was similar to the phenotypes of Gα13 KO mice and Rho kinase (ROCK) KO mice, in which Gα13 and ROCK function downstream of LPARs.^57,58) Therefore, Ishii’s group at Akita University generated DKO mice of two Gα13-coupled receptors, LPAR4 and LPAR6.⁵⁹⁾ The phenotype of Lpar4/Lpar6 DKO mice was quite similar to that of ATX KO mice. They also showed that Lpar4 and Lpar6 are expressed in vascular endothelial cells and activate Yap/Taz transcription factors. LPARs are well conserved in all vertebrates including fish. Interestingly, we recently showed that KO of either ATX KO or Lpar4/Lpar6 DKO, which are lethal in mice, was not lethal in zebrafish.⁶⁰⁾ Detailed time-lapse observations of these mutant zebrafish revealed a caudal vein plexus (CVP), a special vascular plexus structure composed mainly of endothelial cells, was incorrectly formed. In addition, ATX inhibitors disrupted preformed vessels. These observations clearly showed that ATX and LPAR6 play an essential role in the formation and maintenance of the vascular plexus, at least in zebrafish. Interestingly, administering an LPAR6 agonist to zebrafish caused vasoconstriction, and Lpar6 KO mice showed a blunted increase in blood pressure following intravenous administration of LPA. These observations suggest that LPA has a novel role in the contractility of microvessels.

3. SPHINGOSINE 1-PHOSPHATE, S1P

3.1. Structure, Distribution, Pharmacological Actions, Identification of Receptors

Structurally S1P and LPA are similar. The difference is that S1P has a sphingosine backbone while LPA has a glycerol backbone (Fig. 2). Historically, various pharmacological experiments have shown that LPA and S1P share common pharmacological actions such as promoting cell migration, cell morphology changes, and cell proliferation and that they trigger similar cellular responses via GPCRs.⁹⁾ Due to their close structural similarity, researchers had speculated that S1P and LPA share common receptors. However, the first LPA receptor, LPAR1, did not bind and respond to S1P. Meanwhile, Hla’s group at the University of Connecticut (U.S.A.) identified Edg1 as the first S1P receptor.⁶¹⁾ Edg1 is a close homolog of LPAR1/Edg2. In addition, it never reacted with LPA. It is now called SIPR1. The subsequent discoveries of four additional S1P receptors, Edg5/S1PR2, Edg3/S1PR3, Edg6/S1PR4, and Edg8/S1PR5, revealed that eight EDG family members are divided into two subgroups, LPA receptor subgroups (Edg2, 4, 7) and S1P receptor subgroups (Edg1, 3, 5, 6, 8)^9,62) (Fig. 4). Interestingly, there are no S1P receptors for members of the P2Y family, which includes three LPA receptors (LPAR4, 5, 6).

S1P appears to have another role as a second messenger or an intracellular signaling molecule.^63,64) There is some evidence that sphingolipid metabolites, particularly ceramide and S1P, are signaling molecules that regulate a diverse range of cellular processes. Importantly, during these processes, sphingolipid metabolites including sphingomyelin, ceramide, ceramide 1-phosphate, and S1P, can be interconverted. Apparently, the interconversion of sphingolipids is detected in lower organisms that do not possess an S1P receptor, suggesting that S1P has dual roles as an extracellular signaling molecule mediated by S1PRs and as an intracellular signaling molecule.

3.2. S1P-Producing and -Degrading Enzymes, Transporters, and Carrier Proteins

LPA and S1P recognize similar but distinct receptors, but their synthetic routes are quite different (Fig. 3). While LPA is produced extracellularly by degradative reactions, S1P is produced intracellularly by a phosphorylation reaction. Thus, S1P needs energy (ATP) for its production. In addition, to act on receptors, S1P is transported extracellularly via specific transporters. In the late 1990s, Kohama and Spiegel at University of Virginia (U.S.A.) identified two sphingosine kinases capable of producing S1P in vitro from sphingosine by phosphorylation reaction^65,66) (Fig. 3). Two such sphingosine kinases were identified and are now called SphK1 and SphK2.

In 2009, Kawahara et al. identified an S1P transporter, Spns2 (Fig. 3), using zebrafish genetics.⁶⁷⁾ They noted that zebrafish mutants lacking a gene encoding a transporter-like molecule showed a phenotype similar to that of S1PR2 mutants. The gene encodes a functional S1P transporter, Spns2, that releases S1P extracellularly. Spns2 is responsible for S1P release from endothelial cells, but S1P transporters on other S1P-producing cells, such as red blood cells, remained unidentified. Recently, Nguyen at National University of Singapore and Nishi at University of Osaka independently identified the second S1P receptor Mfsd2b, which is essential for the release of S1P release from erythrocytes and platelets^68,69) (Fig. 4).

Lipid phosphate phosphatases (LPP) serve as a negative regulator of S1P signaling.³⁷⁾ However, because their substrate specificity is broad, LPPs also serve as negative regulators of other lipid phosphates, including LPA, PA, and C1P. S1P has another degrading enzyme called S1P lyase that is specific to S1P. S1P lyase irreversibly degrades S1P by cleaving an acyl chain of S1P, yielding hexadecenal and ethanolamine phosphate and contributes to the depletion of intracellular S1P (Fig. 4).

Okajima’s group at Gunma University found that S1P is present in high concentrations in the blood, where it mainly binds to high-density lipoprotein (HDL).⁷⁰⁾ Interestingly, S1P appears to be a major component of HDL and is responsible for HDL’s cytoprotective actions toward human umbilical vein endothelial cells. Later, S1P was found to bind to ApoM, an apolipoprotein of HDL⁷¹⁾ (Fig. 4). ApoM is essential for various biological functions of S1P.⁷²⁾

3.3. Biological Roles of S1P via S1P Producing and Degrading Enzymes, Receptors, Transporters, and Carriers

From studies using knockout mice and animals with S1P-related proteins (producing and degrading enzymes, receptors, transporters, and carriers), several pathophysiological roles of S1P have been elucidated, some of which are listed in Table 1.

The best-known function of S1P is probably its vascular stabilizing function. Deletion of the S1pr1 in mice results in lethality beginning at E12.5 due to severe hemorrhage as the result of deficient coverage of vessels by vascular smooth muscle cells, which is necessary for stabilizing the vascular system.⁷³⁾ Sphingosine kinase-null mice (Sphk1 and Sphk2 double KO mice) caused embryonic lethality and severely disturbed angiogenesis with a complete loss of S1P. S1pr1/S1pr2/S1pr3 triple KO embryos displayed a substantially more severe vascular phenotype than did embryos with only S1pr1 deletion.⁷⁴⁾ Thus, S1PR1, S1PR2, and S1PR3 appear to have redundant functions for developing a stable and mature vascular system during embryonic development. S1PR1 mainly couples with Gαi and modulates the trafficking and activation of N-cadherin, which contributes to stabilizing nascent blood vessels by smooth muscle cells.⁷⁵⁾

Another well-known function of S1P is to support the egress of lymphocytes from lymph nodes. This finding was revealed from a study to elucidate the mechanism of action of FTY720, a drug that causes lymphopenia (reduction of lymphocytes in the blood).⁷⁶⁾ FTY720 is particularly effective in autoimmune diseases such as multiple sclerosis. When animals were treated with FTY720, lymphocytes could not egress from the lymph nodes. FTY720 has a structure similar to that of sphingosine. When administered in vivo, it is taken up intracellularly, phosphorylated by SphK2, and secreted extracellularly by Spns2, where it suppresses lymphocyte S1PR1 function.⁷⁷⁾ It was also found that lymphocytes lacking S1PR1 were unable to egress to leave from lymph nodes.⁷⁸⁾ The activity of the S1P-degrading enzyme lyase was high, and S1P concentrations were low in the lymph nodes, and it was assumed that a concentration gradient of S1P existed between the lymph nodes and the lymph fluid with high S1P concentrations. It is now thought that lymphocytes egress to leave from lymph nodes by utilizing the S1P concentration gradient as a chemoattractant.

S1PR2 also has a specific role in B lymphocytes. In B cell lineages, S1PR2 expression is exceptionally high in germinal center (GC) B cells, which further develop into antibody-secreting plasma cells and memory B cells. In the GC but not outside the GC, S1P concentration is low. In the GC, S1PR2 inhibited GC B cell responses to follicular chemoattractants and helped confine the cells to the GC.⁷⁹⁾

Compared to the numerous studies of S1PR1 and S1PR2, only a few studies have examined S1PR3, 4 and 5.⁸⁰⁾ S1PR3 is widely expressed in various cell type and has an inflammation-stimulating activity. S1PR4 is predominantly expressed in immune cells, but it plays a minor role in immune cell trafficking. S1PR5 is a minor S1P receptor but is also expressed in a subpopulation of T cells. Recently, S1PR5 was shown to have a role in T cell infiltration and emigration from peripheral organs by being downregulated in response to specific signals.

4. SUGAR-CONTAINING LPLS

4.1. Structure, Distribution, and Identification of Receptors

In 2007, Sugiura’s group at Teikyo University reported that lysophosphatidylinositol (LPI) activated GPR55.⁸¹⁾ In 2015, our group, in collaboration with Drs. Hirabayashi and Kamiguchi in RIKEN, Japan, identified lysophosphatidylglucose (LPtdGlc) as a ligand for GPR55.⁸²⁾ Sugiura’s group also showed that GPR55 could be activated by lysophosphatidylglycerol (LPG).⁸¹⁾ Interestingly, LPLs with phosphor-galactose and phosphor-mannose do not appear to be ligands of GPR55.^81,83) Several reports have shown that certain cannabinoid ligands interact with GPR55. For example, a potent synthetic agonist of two cannabinoid receptors (CB₁ and CB₂) and a selective CB₂ agonist (JWH015), are potent agonists of GPR55.⁸⁴⁾ However, WIN55212-2, a potent agonist of CB₂, does not activate GPR55.⁸⁵⁾ Considering the two main endocannabinoids, arachidonoyl ethanolamide (AEA) or 2-arachidonilglycerol (2-AG), are not recognized by GPR55, these endocannabinoids and synthetic cannabinoids are not the ligands for GPR55. Interestingly, GPR55 and CB1, which are co-expressed in many tissues, especially in the central nervous system, form heteromers, and affect the downstream signaling with each other.⁸⁶⁾ Thus, at present, LPI and LPtdGlc appear to be potent agonists, and LPG is a weak agonist for GPR55.

LPI and LPG are found in many tissues. PI and PG are probably precursors for LPI and LPG, respectively. Interestingly, there are several lines of evidence that LPI levels increase in cancer. For example, malignant ascites contain higher LPI levels than non-malignant samples, and Kitamura et al. found that LPI and LPG levels were higher in cancerous regions than in noncancerous regions of the colon.^87,88)In vitro studies have also suggested that oncogene-transformed cells contained a high level of LPI compared with non-transformed cells.⁸⁷⁾ These studies suggest that the elevated LPI level contributes to the progression of cancer cells. However, the underlying mechanism has been poorly understood.

4.2. Synthetic Pathways of LPI and LPtdGlc

The synthetic routes of LPI and LPtdGlc remain to be identified. LPI detected in cells and tissues has both saturated and unsaturated fatty acids, indicating the involvement of PLA₁ and PLA₂-type enzymes. Among the several PLA₁ and PLA₂ isozymes, one of them, an intracellular PLA₁ named DDHD1/PA-PLA₁, was suggested to be involved in producing arachidonyl LPI since arachidonyl LPI decreased in Ddhd1 KO mice.⁸⁹⁾ LPtdGlc detected in the brain contained mainly saturated fatty acids, suggesting that some PLA₂s are involved in its synthesis. PtdGlc, a precursor of LPtdGlc, is a unique sugar-containing PLs enriched in the brain.⁹⁰⁾ Analyses of cellular localization of PtdGlc in the brain using a monoclonal antibody specific to PtdGlc showed that it is highly expressed in glial fibrillary acidic protein (GFAP)-positive astroglial cells and radial glial cells during the developmental stages.⁹¹⁾

4.3. GPR55 Has Multiple Roles

As suggested by its widespread expression, GPR55 has multiple functions (Table 1). In the brain, GPR55 is expressed by specific neurons and mediates repulsive guidance of spinal cord sensory axons.⁸²⁾ In this context, LPtdGlc is probably a ligand for GPR55, which is released by radial glia and regulates the targeting of central axon projections as a repulsive factor. GPR55 is also involved in LPI-induced inhibition of the differentiation of bone macrophages and glucose-induced insulin secretion from pancreatic β cells.^92,93) GPR55 also controls the functional differentiation of self-renewing epithelial progenitors for salivation.⁹⁴⁾ At the cellular level, GPR55 couples with Gα12/13 and induces inhibition of neurite outgrowth.⁸²⁾

5. LYSOPS

5.1. Structure, Distribution, and Pharmacological Actions

LysoPS is a lysophospholipid with the amino acid L-serine at its polar head (Fig. 2). LysoPS was reported to be produced by activated rat platelets in vitro.⁹⁵⁾ However, because LysoPS is a minor LPL, the circumstances under which LysoPS is produced, and its presence in vivo are not fully understood. Recent advances in mass spectrometry have made it possible to detect LysoPS in vivo. Such a study indicated that LysoPS is present in plasma at sub-nM concentration but in serum at concentrations of several hundred nM.⁹⁶⁾ The very high concentrations of LysoPS is probably derived from platelets. Interestingly, the major molecular species of LysoPS detected are docosahexaenoic acid (DHA; 22 : 6) and arachidonic acid (20 : 4) as well as stearic acid (18 : 0).⁹⁶⁾ Therefore, in addition to PLA₂, a PLA₁-type enzyme is assumed to be involved in the production of LysoPS.

LysoPS exhibits several pharmacological effects both in vitro and in vivo. The most analyzed of these effects is stimulation of mast cell degranulation. LysoPS enhanced histamine release from rodent mast cells when it was simultaneously added with a molecule that cross-links with the immunoglobulin E (IgE) receptor FcεRI.⁹⁷⁾ This effect is also seen in vivo, where intravenous administration of LysoPS induces anaphylactic shock and a decrease in body temperature.⁴⁾ Such effects have not been seen with other lysophospholipids (LPA, LPC, LPE, LPG, LPI), nor with LysoPS derivatives in which D-serine replaces the usual L-serine. These results strongly suggest that mast cells have LysoPS receptors that strictly recognize the serine residue of LysoPS. Interestingly, the degranulation action of mast cells is induced by one of the LysoPS derivatives, lysophosphatidylthreonine (LPT).⁹⁸⁾ Threonine has a structure similar to that of serine except that it has an additional methyl group on the β-carbon. This suggests that the putative LysoPS receptors on mast cells recognize both LysoPS and LysoPT. Other actions of LysoPS include enhancing neurite outgrowth induced by nerve growth factor (NGF) in PC12 cells, inhibiting human T cell proliferation, inducing fibroblast migration, modulating CYP activation, and promoting phagocytosis of dead cells by macrophages.⁹⁹⁾

5.2. LysoPS Receptors

The above described LysoPS actions are LysoPS-specific. Therefore, it is thought that there are receptors that recognize the entire structure of LysoPS. Recently, our group and Takeda Pharmaceuticals identified several orphan GPCRs as cellular receptors for LysoPS.^100–102) These include LPSR1 (GPR34), LPAR2 (P2Y10), LPSR2L (A630033H20), and LPSR3 (GPR174) (Fig. 5), all belonging to the P2Y family. Interestingly, three of the family (LPAR4, LPAR5, and LPAR6) have high homology to the identified LysoPS receptors. Most of the P2Y family members recognize nucleotides such as ATP, and both nucleotides and LPLs have phosphodiester bonds; thus, P2Y family molecules may recognize these common chemical structures. We have proposed the nomenclature of these GPCRs as LPSR1/LPS₁ (GPR34), LPSR2/LPS₂ (P2Y10), LPSR2L/LPS_2L (A630033H200) and LPSR3/LPS₃ (GPR174), following the nomenclature of the lysophospholipid receptors, respectively.⁷⁾ The following summarizes the information available to date on each of these receptors.

Fig. 5. Production and Action of Lysophosphatidylserine (LysoPS), Lysophosphatidylinositol (LPI) and Lysophosphatidylglucose (LPtdGlc)

Three GPCRs have been identified for LysoPS, whereas one GPCR GPR55 was identified for LPI/LPtdGlc. In contrast to LPA and S1P (Fig. 3), little is known about the synthetic pathways for LysoPS and LPI/LPtdGlc. It has been postulated that LysoPS and LPI/LPtdGlc are produced from their precursors phosphatidylserine (PS) and phosphatidylinositol (PI)/phosphatidylglucose (PtdGlc), respectively. PS-specific PLA₁ (PS-PLA₁) which hydrolyzes PS in a highly specific manner, is a candidate for a LysoPS-producing enzyme (section 5.3.). Because PS-PLA₁ is a secreted enzyme, PS, which usually locates in the inner leaflet of plasma membrane, has to be translocated to the outer leaflet, possibly by some flipases, before it is converted to LysoPS by PS-PLA₁.

5.3. LysoPS Synthetic Pathways

Unlike receptors, how LysoPS is produced is not well understood. Two enzymes have been proposed that arise from the precursor PS. One is a secreted PLA₁ that acts in a PS-specific manner and is named PS-specific PLA₁ (PS-PLA₁)^103–105) (Fig. 5). It also has the name PLA1A. PS-PLA₁ hydrolyses PS exposed on the cell surface, especially apoptotic cells, to produce LysoPS with unsaturated fatty acids at the sn-2 position. In vitro, PS-PLA₁ protein activates degranulation reaction in mast cells and LysoPS receptors expressed on the cell.¹⁰⁶⁾ However, the function of PS-PLA₁ at the animal level is not well understood. In human clinical practice, plasma levels of PS-PLA₁ are elevated in autoimmune diseases and may be involved in some immune regulation.¹⁰⁷⁾

5.4. Roles of LysoPS as Immune Modulators Revealed by Receptor KO Mice

Several lines of evidence have suggested immune-modulatory roles of LysoPS through its receptors (Table 1). Lpsr1 (Gpr34)-deficient mice are healthy. However, sensitizing them with methylated bovine serum albumin or subjecting them to bacterial infection strongly induced cytokine production and suppressed inflammation compared to wild-type mice.¹⁰⁸⁾Lpsr1 KO mice have also been shown to be vulnerable to infection. Lpsr1, which is highly expressed by microglia, exacerbates neuropathic pain, and accelerates the phagocytic activity of the cells in mice.¹⁰⁹⁾

LysoPS suppressed immune responses by activating LPSR3 (GPR174), and LPSR2 (P2Y10) expressed in both CD4 T and B cells. For example, we reported that LysoPS suppressed IL-2 production by T cells via LPSR3.¹¹⁰⁾ Interestingly, T cell activation increased the generation of LysoPS, which may account for higher IL-2 production by Lpsr3-deficient cells. Because Gαs-deficient cells showed similar up-regulation of IL-2 and LPSR3 couples with Gαs, LysoPS represents one of the major Gαs-dependent ligands produced by T cell cultures that can affect T cell activation. Interestingly, Lpsr3 is encoded by X-chromosome and suppresses the formation of germinal centers, i.e., suppresses B cells maturation, in male, but not female, mice.¹¹¹⁾ Recently, LPSR2 was reported to facilitate chemokine-induced CD4 T cell migration through autocrine/paracrine production of LysoPS.¹¹²⁾

6. PROSPECT

This review gives a brief history of the advances made in the understanding of LPL mediators, including their receptors, metabolic enzymes, transporters, and pathophysiological roles, in which we highlight the many contributions of Japanese researchers. Apparently, at least four structurally distinct LPLs are recognized by GPCR-type receptors as ligands and modulate various pathophysiological functions, including immune responses. They are an active field of research, especially in biomarker and drug discovery studies. Further researches are expected to develop in the future.

Conflict of Interest

The authors declare no conflict of interest.

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