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International Immunology Aug 2019AbstractSphingosine 1-phosphate (S1P), a sphingolipid mediator, regulates various cellular functions via high-affinity G protein-coupled receptors, S1P1-5. The S1P-S1P... (Review)
Review
AbstractSphingosine 1-phosphate (S1P), a sphingolipid mediator, regulates various cellular functions via high-affinity G protein-coupled receptors, S1P1-5. The S1P-S1P receptor signaling system plays important roles in lymphocyte trafficking and maintenance of vascular integrity, thus contributing to the regulation of complex inflammatory processes. S1P is enriched in blood and lymph while maintained low in intracellular or interstitial fluids, creating a steep S1P gradient that is utilized to facilitate efficient egress of lymphocytes from lymphoid organs. Blockage of the S1P-S1P receptor signaling system results in a marked decrease in circulating lymphocytes because of a failure of lymphocyte egress from lymphoid organs. This provides a basis of immunomodulatory drugs targeting S1P1 receptor such as FTY720, an immunosuppressive drug approved in 2010 as the first oral treatment for relapsing-remitting multiple sclerosis. The S1P-S1P receptor signaling system also plays important roles in maintenance of vascular integrity since it suppresses sprouting angiogenesis and regulates vascular permeability. Dysfunction of the S1P-S1P receptor signaling system results in various vascular defects, such as exaggerated angiogenesis in developing retina and augmented inflammation due to increased permeability. Endothelial-specific deletion of S1P1 receptor in mice fed high-fat diet leads to increased formation of atherosclerotic lesions. This review highlights the importance of the S1P-S1P receptor signaling system in inflammatory processes. We also describe our recent findings regarding a specific S1P chaperone, apolipoprotein M, that anchors to high-density lipoprotein and contributes to shaping the endothelial-protective and anti-inflammatory properties of high-density lipoprotein.
Topics: Animals; Humans; Inflammation; Lysophospholipids; Signal Transduction; Sphingosine; Sphingosine-1-Phosphate Receptors
PubMed: 31049553
DOI: 10.1093/intimm/dxz037 -
Journal of Neuroinflammation Apr 2020In the extracellular environment, lysophosphatidic acid (LPA) species are generated via autotaxin (ATX)-mediated hydrolysis of lysophospholipid precursors. Members of...
BACKGROUND
In the extracellular environment, lysophosphatidic acid (LPA) species are generated via autotaxin (ATX)-mediated hydrolysis of lysophospholipid precursors. Members of the LPA family are potent lipid mediators transmitting signals via six different G protein-coupled LPA receptors (LPAR1-6). The LPA signaling axis is indispensable for brain development and function of the nervous system; however, during damage of the central nervous system, LPA levels can increase and aberrant signaling events counteract brain function. Here, we investigated regulation of the ATX/LPA/LPAR axis in response to lipopolysaccharide-induced systemic inflammation in mice and potential neurotoxic polarization programs in LPA-activated primary murine microglia.
METHODS
In vivo, LPAR1-6 expression was established by qPCR in whole murine brain homogenates and in FACS-sorted microglia. ELISAs were used to quantitate LPA concentrations in the brain and cyto-/chemokine secretion from primary microglia in vitro. Transcription factor phosphorylation was analyzed by immunoblotting, and plasma membrane markers were analyzed by flow cytometry. We used MAPK inhibitors to study signal integration by the JNK, p38, and ERK1/2 branches in response to LPA-mediated activation of primary microglia.
RESULTS
Under acute and chronic inflammatory conditions, we observed a significant increase in LPA concentrations and differential regulation of LPAR, ATX (encoded by ENPP2), and cytosolic phospholipase A2 (encoded by PLA2G4A) gene expression in the brain and FACS-sorted microglia. During pathway analyses in vitro, the use of specific MAPK antagonists (SP600125, SB203580, and PD98059) revealed that JNK and p38 inhibition most efficiently attenuated LPA-induced phosphorylation of proinflammatory transcription factors (STAT1 and -3, p65, and c-Jun) and secretion of IL-6 and TNFα. All three inhibitors decreased LPA-mediated secretion of IL-1β, CXCL10, CXCL2, and CCL5. The plasma membrane marker CD40 was solely inhibited by SP600125 while all three inhibitors affected expression of CD86 and CD206. All MAPK antagonists reduced intracellular COX-2 and Arg1 as well as ROS and NO formation, and neurotoxicity of microglia-conditioned media.
CONCLUSION
In the present study, we show that systemic inflammation induces aberrant ATX/LPA/LPAR homeostasis in the murine brain. LPA-mediated polarization of primary microglia via MAPK-dependent pathways induces features reminiscent of a neurotoxic phenotype.
Topics: Animals; Inflammation; Lysophospholipids; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Microglia; Phosphoric Diester Hydrolases; Receptors, Lysophosphatidic Acid
PubMed: 32326963
DOI: 10.1186/s12974-020-01809-1 -
International Journal of Molecular... Jan 2011Phospholipase A(1) (PLA(1)) is an enzyme that hydrolyzes phospholipids and produces 2-acyl-lysophospholipids and fatty acids. This lipolytic activity is conserved in a... (Review)
Review
Phospholipase A(1) (PLA(1)) is an enzyme that hydrolyzes phospholipids and produces 2-acyl-lysophospholipids and fatty acids. This lipolytic activity is conserved in a wide range of organisms but is carried out by a diverse set of PLA(1) enzymes. Where their function is known, PLA(1)s have been shown to act as digestive enzymes, possess central roles in membrane maintenance and remodeling, or regulate important cellular mechanisms by the production of various lysophospholipid mediators, such as lysophosphatidylserine and lysophosphatidic acid, which in turn have multiple biological functions.
Topics: Animals; Humans; Lysophospholipids; Phospholipases A; Phospholipases A1; Substrate Specificity; Type C Phospholipases
PubMed: 21340002
DOI: 10.3390/ijms12010588 -
Annual Review of Pathology Jan 2022Lysophospholipids, exemplified by lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P), are produced by the metabolism and perturbation of biological membranes.... (Review)
Review
Lysophospholipids, exemplified by lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P), are produced by the metabolism and perturbation of biological membranes. Both molecules are established extracellular lipid mediators that signal via specific G protein-coupled receptors in vertebrates. This widespread signaling axis regulates the development, physiological functions, and pathological processes of all organ systems. Indeed, recent research into LPA and S1P has revealed their important roles in cellular stress signaling, inflammation, resolution, and host defense responses. In this review, we focus on how LPA regulates fibrosis, neuropathic pain, abnormal angiogenesis, endometriosis, and disorders of neuroectodermal development such as hydrocephalus and alopecia. In addition, we discuss how S1P controls collective behavior, apoptotic cell clearance, and immunosurveillance of cancers. Advances in lysophospholipid research have led to new therapeutics in autoimmune diseases, with many more in earlier stages of development for a wide variety of diseases, such as fibrotic disorders, vascular diseases, and cancer.
Topics: Animals; Female; Fibrosis; Humans; Lysophospholipids; Neoplasms; Signal Transduction
PubMed: 34813354
DOI: 10.1146/annurev-pathol-050420-025929 -
Biomolecules Oct 2020The phospholipase A (PLA) superfamily contains more than 50 enzymes in mammals that are subdivided into several distinct families on a structural and biochemical basis.... (Review)
Review
The phospholipase A (PLA) superfamily contains more than 50 enzymes in mammals that are subdivided into several distinct families on a structural and biochemical basis. In principle, PLA has the capacity to hydrolyze the -2 position of glycerophospholipids to release fatty acids and lysophospholipids, yet several enzymes in this superfamily catalyze other reactions rather than or in addition to the PLA reaction. PLA enzymes play crucial roles in not only the production of lipid mediators, but also membrane remodeling, bioenergetics, and body surface barrier, thereby participating in a number of biological events. Accordingly, disturbance of PLA-regulated lipid metabolism is often associated with various diseases. This review updates the current state of understanding of the classification, enzymatic properties, and biological functions of various enzymes belonging to the PLA superfamily, focusing particularly on the novel roles of PLAs in vivo.
Topics: Animals; Cell Membrane; Fatty Acids; Glycerophospholipids; Humans; Lipid Metabolism; Lysophospholipids; Mammals; Phospholipases A2
PubMed: 33086624
DOI: 10.3390/biom10101457 -
Progress in Lipid Research Nov 2020Lipids are abundant and play essential roles in human health and disease. The main functions of lipids are building blocks for membrane biogenesis. However, lipids are... (Review)
Review
Lipids are abundant and play essential roles in human health and disease. The main functions of lipids are building blocks for membrane biogenesis. However, lipids are also metabolized to produce signaling molecules. Here, we discuss the emerging roles of circulating lysophospholipids. These lysophospholipids consist of lysoglycerophospholipids and lysosphingolipids. They are both present in cells at low concentration, but their concentrations in extracellular fluids are significantly higher. The biological functions of some of these lysophospholipids have been recently revealed. Remarkably, some of the lysophospholipids play pivotal signaling roles as well as being precursors for membrane biogenesis. Revealing how circulating lysophospholipids are produced, released, transported, and utilized in multi-organ systems is critical to understand their functions. The discovery of enzymes, carriers, transporters, and membrane receptors for these lysophospholipids has shed light on their physiological significance. In this review, we summarize the biological roles of these lysophospholipids via discussing about the proteins regulating their functions. We also discuss about their potential impacts to human health and diseases.
Topics: Animals; Biomarkers; Carrier Proteins; Humans; Lysophospholipids; Signal Transduction
PubMed: 33068601
DOI: 10.1016/j.plipres.2020.101068 -
Pharmacology & Therapeutics Jun 2023Lysophosphatidic acid (LPA) is a simple phospholipid consisting of a phosphate group, glycerol moiety, and only one hydrocarbon chain. Despite its simple chemical... (Review)
Review
Lysophosphatidic acid (LPA) is a simple phospholipid consisting of a phosphate group, glycerol moiety, and only one hydrocarbon chain. Despite its simple chemical structure, LPA plays an important role as an essential bioactive signaling molecule via its specific six G protein-coupled receptors, LPA. Recent studies, especially those using genetic tools, have revealed diverse physiological and pathological roles of LPA and LPA receptors in almost every organ system. Furthermore, many studies are illuminating detailed mechanisms to orchestrate multiple LPA receptor signaling pathways and to facilitate their coordinated function. Importantly, these extensive "bench" works are now translated into the "bedside" as exemplified by approaches targeting LPA signaling to combat fibrotic diseases. In this review, we discuss the physiological and pathological roles of LPA signaling and their implications for clinical application by focusing on findings revealed by in vivo studies utilizing genetic tools targeting LPA receptors.
Topics: Humans; Receptors, Lysophosphatidic Acid; Lysophospholipids; Signal Transduction; Glycerol
PubMed: 37080433
DOI: 10.1016/j.pharmthera.2023.108421 -
Proceedings of the Japan Academy.... 2018Lysophospholipids (LPLs), such as lysophosphatidic acid (LPA), sphingosine 1-phosphate (S1P), and lysophosphatidylserine (LysoPS), are attracting attention as... (Review)
Review
Lysophospholipids (LPLs), such as lysophosphatidic acid (LPA), sphingosine 1-phosphate (S1P), and lysophosphatidylserine (LysoPS), are attracting attention as second-generation lipid mediators. In our laboratory, the functional roles of these lipid mediators and the mechanisms by which the levels of these mediators are regulated in vivo have been studied. Based on these studies, the clinical introduction of assays for LPLs and related proteins has been pursued and will be described in this review. Although assays of these lipids themselves are possible, autotaxin (ATX), apolipoprotein M (ApoM), and phosphatidylserine-specific phospholipase A (PS-PLA) are more promising as alternate biomarkers for LPA, S1P, and LysoPS, respectively. Presently, ATX, which produces LPA through its lysophospholipase D activity, has been shown to be a useful laboratory test for the diagnosis and staging of liver fibrosis, whereas PS-PLA and ApoM are considered to be promising clinical markers reflecting the in vivo actions induced by LysoPS and S1P.
Topics: Animals; Body Fluids; Humans; Laboratories; Lysophospholipids
PubMed: 30541965
DOI: 10.2183/pjab.94.025 -
Frontiers in Bioscience (Landmark... Jan 2016Lysophospholipids (LPLs) are bioactive lipid-derived signaling molecules generated by the enzymatic and chemical processes of regiospecific phospholipases on substrates... (Review)
Review
Lysophospholipids (LPLs) are bioactive lipid-derived signaling molecules generated by the enzymatic and chemical processes of regiospecific phospholipases on substrates such as membrane phospholipids (PLs) and sphingolipids (SLs). They play a major role as extracellular mediators by activating G-protein coupled receptors (GPCRs) and stimulating diverse cellular responses from their signaling pathways. LPLs are involved in various pathologies of the vasculature system including coronary heart disease and hypertension. Many studies suggest the importance of LPLs in their association with the development of atherosclerosis, a chronic and severe vascular disease. This paper focuses on the pathophysiological effects of different lysophospholipids on atherosclerosis, which may promote the pathogenesis of myocardial infarction and strokes. Their atherogenic biological activities take place in vascular endothelial cells, vascular smooth muscle cells, fibroblasts, monocytes and macrophages, dendritic cells, T-lymphocytes, platelets, etc.
Topics: Atherosclerosis; Humans; Lymphocytes; Lysophospholipids; Macrophages; Muscle, Smooth, Vascular; Receptors, G-Protein-Coupled
PubMed: 26709762
DOI: 10.2741/4377 -
Biomolecules Sep 2020Lipid phosphate phosphatases (LPPs) are a group of three enzymes (LPP1-3) that belong to a phospholipid phosphatase (PLPP) family. The LPPs dephosphorylate a wide... (Review)
Review
Lipid phosphate phosphatases (LPPs) are a group of three enzymes (LPP1-3) that belong to a phospholipid phosphatase (PLPP) family. The LPPs dephosphorylate a wide spectrum of bioactive lipid phosphates, among which lysophosphatidate (LPA) and sphingosine 1-phosphate (S1P) are two important extracellular signaling molecules. The LPPs are integral membrane proteins, which are localized on plasma membranes and intracellular membranes, including the endoplasmic reticulum and Golgi network. LPPs regulate signaling transduction in cancer cells and demonstrate different effects in cancer progression through the breakdown of extracellular LPA and S1P and other intracellular substrates. This review is intended to summarize an up-to-date understanding about the functions of LPPs in cancers.
Topics: Animals; Cell Membrane; Humans; Lysophospholipids; Neoplasms; Phosphatidate Phosphatase; Signal Transduction; Sphingosine; Up-Regulation
PubMed: 32887262
DOI: 10.3390/biom10091263