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Science (New York, N.Y.) Oct 2019Sphingosine 1-phosphate (S1P), a metabolic product of cell membrane sphingolipids, is bound to extracellular chaperones, is enriched in circulatory fluids, and binds to... (Review)
Review
Sphingosine 1-phosphate (S1P), a metabolic product of cell membrane sphingolipids, is bound to extracellular chaperones, is enriched in circulatory fluids, and binds to G protein-coupled S1P receptors (S1PRs) to regulate embryonic development, postnatal organ function, and disease. S1PRs regulate essential processes such as adaptive immune cell trafficking, vascular development, and homeostasis. Moreover, S1PR signaling is a driver of multiple diseases. The past decade has witnessed an exponential growth in this field, in part because of multidisciplinary research focused on this lipid mediator and the application of S1PR-targeted drugs in clinical medicine. This has revealed fundamental principles of lysophospholipid mediator signaling that not only clarify the complex and wide ranging actions of S1P but also guide the development of therapeutics and translational directions in immunological, cardiovascular, neurological, inflammatory, and fibrotic diseases.
Topics: Animals; Apolipoproteins M; Autoimmune Diseases; Cardiovascular Diseases; Cardiovascular Physiological Phenomena; Cardiovascular System; Central Nervous System; Drug Development; Fibrosis; Homeostasis; Humans; Immune System Phenomena; Lysophospholipids; Mice; Molecular Chaperones; Neurodegenerative Diseases; Signal Transduction; Sphingosine; Sphingosine-1-Phosphate Receptors
PubMed: 31624181
DOI: 10.1126/science.aar5551 -
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 -
Nature Immunology Feb 2023Metastasis is the leading cause of cancer-related deaths and myeloid cells are critical in the metastatic microenvironment. Here, we explore the implications of...
Metastasis is the leading cause of cancer-related deaths and myeloid cells are critical in the metastatic microenvironment. Here, we explore the implications of reprogramming pre-metastatic niche myeloid cells by inducing trained immunity with whole beta-glucan particle (WGP). WGP-trained macrophages had increased responsiveness not only to lipopolysaccharide but also to tumor-derived factors. WGP in vivo treatment led to a trained immunity phenotype in lung interstitial macrophages, resulting in inhibition of tumor metastasis and survival prolongation in multiple mouse models of metastasis. WGP-induced trained immunity is mediated by the metabolite sphingosine-1-phosphate. Adoptive transfer of WGP-trained bone marrow-derived macrophages reduced tumor lung metastasis. Blockade of sphingosine-1-phosphate synthesis and mitochondrial fission abrogated WGP-induced trained immunity and its inhibition of lung metastases. WGP also induced trained immunity in human monocytes, resulting in antitumor activity. Our study identifies the metabolic sphingolipid-mitochondrial fission pathway for WGP-induced trained immunity and control over metastasis.
Topics: Animals; Mice; Humans; Trained Immunity; Macrophages; Lysophospholipids; Monocytes; Lung Neoplasms; beta-Glucans; Tumor Microenvironment
PubMed: 36604547
DOI: 10.1038/s41590-022-01388-8 -
Drugs Jun 2021Sphingosine-1-phosphate (S1P) is a bioactive lipid metabolite that exerts its actions by engaging 5 G-protein-coupled receptors (S1PR1-S1PR5). S1P receptors are involved... (Review)
Review
Sphingosine-1-phosphate (S1P) is a bioactive lipid metabolite that exerts its actions by engaging 5 G-protein-coupled receptors (S1PR1-S1PR5). S1P receptors are involved in several cellular and physiological events, including lymphocyte/hematopoietic cell trafficking. An S1P gradient (low in tissues, high in blood), maintained by synthetic and degradative enzymes, regulates lymphocyte trafficking. Because lymphocytes live long (which is critical for adaptive immunity) and recirculate thousands of times, the S1P-S1PR pathway is involved in the pathogenesis of immune-mediated diseases. The S1PR1 modulators lead to receptor internalization, subsequent ubiquitination, and proteasome degradation, which renders lymphocytes incapable of following the S1P gradient and prevents their access to inflammation sites. These drugs might also block lymphocyte egress from lymph nodes by inhibiting transendothelial migration. Targeting S1PRs as a therapeutic strategy was first employed for multiple sclerosis (MS), and four S1P modulators (fingolimod, siponimod, ozanimod, and ponesimod) are currently approved for its treatment. New S1PR modulators are under clinical development for MS, and their uses are being evaluated to treat other immune-mediated diseases, including inflammatory bowel disease (IBD), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and psoriasis. A clinical trial in patients with COVID-19 treated with ozanimod is ongoing. Ozanimod and etrasimod have shown promising results in IBD; while in phase 2 clinical trials, ponesimod has shown improvement in 77% of the patients with psoriasis. Cenerimod and amiselimod have been tested in SLE patients. Fingolimod, etrasimod, and IMMH001 have shown efficacy in RA preclinical studies. Concerns relating to S1PR modulators are leukopenia, anemia, transaminase elevation, macular edema, teratogenicity, pulmonary disorders, infections, and cardiovascular events. Furthermore, S1PR modulators exhibit different pharmacokinetics; a well-established first-dose event associated with S1PR modulators can be mitigated by gradual up-titration. In conclusion, S1P modulators represent a novel and promising therapeutic strategy for immune-mediated diseases.
Topics: Animals; Humans; Immune System Diseases; Lysophospholipids; Multiple Sclerosis; Pharmaceutical Preparations; Signal Transduction; Sphingosine
PubMed: 33983615
DOI: 10.1007/s40265-021-01528-8 -
Pharmacological Research Jun 2020Sphingosine-1-phosphate (S1P) is a signaling lipid, synthetized by sphingosine kinases (SPHK1 and SPHK2), that affects cardiovascular function in various ways. S1P... (Review)
Review
Sphingosine-1-phosphate (S1P) is a signaling lipid, synthetized by sphingosine kinases (SPHK1 and SPHK2), that affects cardiovascular function in various ways. S1P signaling is complex, particularly since its molecular action is reliant on the differential expression of its receptors (S1PR1, S1PR2, S1PR3, S1PR4, S1PR5) within various tissues. Significance of this sphingolipid is manifested early in vertebrate development as certain defects in S1P signaling result in embryonic lethality due to defective vasculo- or cardiogenesis. Similar in the mature organism, S1P orchestrates both physiological and pathological processes occurring in the heart and vasculature of higher eukaryotes. S1P regulates cell fate, vascular tone, endothelial function and integrity as well as lymphocyte trafficking, thus disbalance in its production and signaling has been linked with development of such pathologies as arterial hypertension, atherosclerosis, endothelial dysfunction and aberrant angiogenesis. Number of signaling mechanisms are critical - from endothelial nitric oxide synthase through STAT3, MAPK and Akt pathways to HDL particles involved in redox and inflammatory balance. Moreover, S1P controls both acute cardiac responses (cardiac inotropy and chronotropy), as well as chronic processes (such as apoptosis and hypertrophy), hence numerous studies demonstrate significance of S1P in the pathogenesis of hypertrophic/fibrotic heart disease, myocardial infarction and heart failure. This review presents current knowledge concerning the role of S1P in the cardiovascular system, as well as potential therapeutic approaches to target S1P signaling in cardiovascular diseases.
Topics: Animals; Cardiovascular Diseases; Cardiovascular System; Embryonic Development; Hemodynamics; Humans; Lysophospholipids; Neovascularization, Physiologic; Receptors, Lysosphingolipid; Signal Transduction; Sphingosine
PubMed: 32278039
DOI: 10.1016/j.phrs.2020.104793 -
Immunity Jun 2021Neutrophils migrate rapidly to damaged tissue and play critical roles in host defense and tissue homeostasis. Here we investigated the mechanisms whereby neutrophils...
Neutrophils migrate rapidly to damaged tissue and play critical roles in host defense and tissue homeostasis. Here we investigated the mechanisms whereby neutrophils participate in tissue repair. In an intestinal epithelia injury model, neutrophil depletion exacerbated colitis and associated with reduced interleukin (IL)-22 and limited activation of type 3 innate lymphoid cells (ILC3s). Co-culture with neutrophils activated ILC3s in a manner dependent on neutrophil apoptosis. Metabolomic analyses revealed that lysophosphatidylserine (LysoPS) from apoptotic neutrophils directly stimulated ILC3 activation. ILC3-specific deletion of Gpr34, encoding the LysoPS receptor GPR34, or inhibition of downstream PI3K-AKT or ERK suppressed IL-22 production in response to apoptotic neutrophils. Gpr34 mice exhibited compromised ILC3 activation and tissue repair during colon injury, and neutrophil depletion abrogated these defects. GPR34 deficiency in ILC3s limited IL-22 production and tissue repair in vivo in settings of colon and skin injury. Thus, GPR34 is an ILC3-expressed damage-sensing receptor that triggers tissue repair upon recognition of dying neutrophils.
Topics: Animals; Apoptosis; Cells, Cultured; Colitis; Colon; Homeostasis; Humans; Immunity, Innate; Interleukins; Intestinal Mucosa; Lymphocytes; Lysophospholipids; Mice; Mice, Inbred C57BL; Mice, Knockout; Neutrophils; Phosphatidylinositol 3-Kinases; Receptors, Lysophospholipid; Interleukin-22
PubMed: 34107271
DOI: 10.1016/j.immuni.2021.05.007 -
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 -
BMJ Open Respiratory Research Dec 2021Idiopathic pulmonary fibrosis (IPF) and non-IPF, progressive fibrotic interstitial lung diseases (PF-ILD), are associated with a progressive loss of lung function and a... (Randomized Controlled Trial)
Randomized Controlled Trial
Phase 2 trial design of BMS-986278, a lysophosphatidic acid receptor 1 (LPA) antagonist, in patients with idiopathic pulmonary fibrosis (IPF) or progressive fibrotic interstitial lung disease (PF-ILD).
INTRODUCTION
Idiopathic pulmonary fibrosis (IPF) and non-IPF, progressive fibrotic interstitial lung diseases (PF-ILD), are associated with a progressive loss of lung function and a poor prognosis. Treatment with antifibrotic agents can slow, but not halt, disease progression, and treatment discontinuation because of adverse events is common. Fibrotic diseases such as these can be mediated by lysophosphatidic acid (LPA), which signals via six LPA receptors (LPA). Signalling via LPA appears to be fundamental in the pathogenesis of fibrotic diseases. BMS-986278, a second-generation LPA antagonist, is currently in phase 2 development as a therapy for IPF and PF-ILD.
METHODS AND ANALYSIS
This phase 2, randomised, double-blind, placebo-controlled, parallel-group, international trial will include adults with IPF or PF-ILD. The trial will consist of a 42-day screening period, a 26-week placebo-controlled treatment period, an optional 26-week active-treatment extension period, and a 28-day post-treatment follow-up. Patients in both the IPF (n=240) and PF-ILD (n=120) cohorts will be randomised 1:1:1 to receive 30 mg or 60 mg BMS-986278, or placebo, administered orally two times per day for 26 weeks in the placebo-controlled treatment period. The primary endpoint is rate of change in per cent predicted forced vital capacity from baseline to week 26 in the IPF cohort.
ETHICS AND DISSEMINATION
This study will be conducted in accordance with Good Clinical Practice guidelines, Declaration of Helsinki principles, and local ethical and legal requirements. Results will be reported in a peer-reviewed publication.
TRIAL REGISTRATION NUMBER
NCT04308681.
Topics: Adult; Humans; Idiopathic Pulmonary Fibrosis; Lysophospholipids; Receptors, Lysophosphatidic Acid; Vital Capacity
PubMed: 34969771
DOI: 10.1136/bmjresp-2021-001026 -
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 -
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