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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 -
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 -
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 -
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 -
Biomolecules May 2023Sphingosine-1-phosphate (S1P) is an important sphingolipid molecule involved in regulating cardiovascular functions in physiological and pathological conditions by... (Review)
Review
Sphingosine-1-phosphate (S1P) is an important sphingolipid molecule involved in regulating cardiovascular functions in physiological and pathological conditions by binding and activating the three G protein-coupled receptors (S1PR1, S1PR2, and S1PR3) expressed in endothelial and smooth muscle cells, as well as cardiomyocytes and fibroblasts. It exerts its actions through various downstream signaling pathways mediating cell proliferation, migration, differentiation, and apoptosis. S1P is essential for the development of the cardiovascular system, and abnormal S1P content in the circulation is involved in the pathogenesis of cardiovascular disorders. This article reviews the effects of S1P on cardiovascular function and signaling mechanisms in different cell types in the heart and blood vessels under diseased conditions. Finally, we look forward to more clinical findings with approved S1PR modulators and the development of S1P-based therapies for cardiovascular diseases.
Topics: Humans; Receptors, Lysosphingolipid; Sphingosine-1-Phosphate Receptors; Cardiovascular Diseases; Sphingosine; Lysophospholipids
PubMed: 37238688
DOI: 10.3390/biom13050818 -
Molecular and Cellular Endocrinology Mar 2022Sphingolipids are essential lipid components in the intestinal epithelial cells (IEC) along the intestinal tract. They play crucial roles in maintaining barrier... (Review)
Review
Sphingolipids are essential lipid components in the intestinal epithelial cells (IEC) along the intestinal tract. They play crucial roles in maintaining barrier integrity, regulating nutrient absorption, and acting as signaling molecules to regulate regeneration and differentiation of intestinal mucosa (Kurek et al., 2012). Ceramide is the central sphingolipid species and the precursor of all complex sphingolipids and other downstream simple intermediates like sphingosine (SPH), ceramide-1-phosphate (C-1-P), and sphingosine-1-phosphate (S-1-P). It is also a critical signaling molecule regulating numerous physiologic and pathologic processes. This review will summarize the metabolism of ceramides in the gut and their regulation in inflammatory bowel diseases and colorectal cancer.
Topics: Ceramides; Humans; Inflammatory Bowel Diseases; Intestinal Mucosa; Lysophospholipids; Signal Transduction; Sphingolipids; Sphingosine
PubMed: 34998898
DOI: 10.1016/j.mce.2022.111554 -
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