scholarly journals Human and Mouse Eosinophils Differ in Their Ability to Biosynthesize Eicosanoids, Docosanoids, the Endocannabinoid 2-Arachidonoyl-glycerol and Its Congeners

Cells ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 141
Author(s):  
Anne-Sophie Archambault ◽  
Julyanne Brassard ◽  
Émilie Bernatchez ◽  
Cyril Martin ◽  
Vincenzo Di Marzo ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
Biosynthetic Pathway ◽  
Lipid Mediators ◽  
Lipid Mediator ◽  
Bioactive Lipids ◽  
Eosinophilic Asthma ◽  
Asthmatic Response ◽  
Pharmacological Targets ◽  
Arachidonoyl Glycerol ◽  
Human And Mouse

High eosinophil (EOS) counts are a key feature of eosinophilic asthma. EOS notably affect asthmatic response by generating several lipid mediators. Mice have been utilized in hopes of defining new pharmacological targets to treat asthma. However, many pinpointed targets in mice did not translate into clinics, underscoring that key differences exist between the two species. In this study, we compared the ability of human (h) and mouse (m) EOS to biosynthesize key bioactive lipids derived from arachidonic acid (AA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). hEOS were isolated from the blood of healthy subjects and mild asthmatics, while mEOSs were differentiated from the bone marrow. EOSs were treated with fatty acids and lipid mediator biosynthesis assessed by LC-MS/MS. We found that hEOS biosynthesized leukotriene (LT) C4 and LTB4 in a 5:1 ratio while mEOS almost exclusively biosynthesized LTB4. The biosynthesis of the 15-lipoxygenase (LO) metabolites 15-HETE and 12-HETE also differed, with a 15-HETE:12-HETE ratio of 6.3 for hEOS and 0.727 for mEOS. EOS biosynthesized some specialized pro-resolving mediators, and the levels from mEOS were 9-times higher than those of hEOS. In contrast, hEOS produced important amounts of the endocannabinoid 2-arachidonoyl-glycerol (2-AG) and its congeners from EPA and DHA, a biosynthetic pathway that was up to ~100-fold less prominent in mEOS. Our data show that hEOS and mEOS biosynthesize the same lipid mediators but in different amounts. Compared to asthmatics, mouse models likely have an amplified involvement of LTB4 and specialized pro-resolving mediators and a diminished impact of the endocannabinoid 2-arachidonoyl-glycerol and its congeners.

scholarly journals Interleukin 3-dependent mediator release in basophils triggered by C5a.

1989 ◽  
Vol 170 (2) ◽  
pp. 467-479 ◽  
Author(s):  
Y Kurimoto ◽  
A L de Weck ◽  
C A Dahinden
Keyword(s):  
Time Course ◽  
Lipid Mediators ◽  
Mediator Release ◽  
Lipid Mediator ◽  
Cell Fractionation ◽  
Leukotriene C4 ◽  
Bioactive Lipids ◽  
Anaphylatoxin C5a ◽  
Dose Dependent

The anaphylatoxin C5a is a potent trigger for basophil degranulations, but in contrast to IgE-dependent basophil activation, it does not result in the synthesis of sulfidoleukotrienes (leukotriene C4/D4/E4). Thus, degranulation and the generation of lipid mediators are separately regulated cellular responses. Exposure of human blood basophils to the cytokine IL-3 alone does not induce the release of histamine in cells from most donors and never leads to the generation of LTC4, indicating that IL-3 is not a direct agonist for basophil mediator release. However, preincubation of basophils with IL-3 enhances the degranulation response to C5a. Most importantly, IL-3 "primes" basophils to release large amounts of leukotriene C4 after challenge with C5a (mean of 50 gp LTC4 per nanograms cellular histamine), while neither peptide alone is capable of inducing the formation of bioactive lipids. This effect is dose dependent, occurring at IL-3 concentrations considerably lower than are required to stimulate the growth of bone marrow progenitor cells. IL-3 affects the extent but not the time course of basophil degranulation, and leukotriene release of cells sequentially exposed to IL-3 and C5a occurs very rapidly concomitant with degranulation. A preincubation of the basophils with IL-3 is strictly required for C5a-induced LTC4 synthesis, but not for an enhancement of degranulation. Priming for C5a-induced lipid mediator generation occurs rapidly after exposure of the cells to IL-3, starting at 1 min and reaching maximal effects at 5 min, but this altered state of responsiveness is relatively long lasting. Cell fractionation studies indicate that the basophil is the source of lipid mediators and that IL-3 affects the basophil response directly. This study demonstrates that IL-3 is a potent modifier of effector functions of mature basophils; this is possibly of greater in vivo significance than its growth factor properties. The large amounts of LTC4 formed after triggering of IL-3-primed basophils may not only enhance but also qualitatively change the pathophysiological consequences of complement activation, and this might be important in the pathogenesis of immediate type hypersensitivity reactions, shock syndromes, and inflammation.

Quantitative profiling of inflammatory and pro-resolving lipid mediators in human adolescents and mouse plasma using UHPLC-MS/MS

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Ivan Hartling ◽  
Alessio Cremonesi ◽  
Ester Osuna ◽  
Phing-How Lou ◽  
Eliana Lucchinetti ◽  
...  
Keyword(s):  
Human Plasma ◽  
Lipid Mediators ◽  
Lipid Mediator ◽  
Prostaglandin D2 ◽  
Reference Ranges ◽  
Good Precision ◽  
Plasma Samples ◽  
Omega 3 ◽  
Bioactive Lipids ◽  
Blood Draw

Abstract Objectives Lipid mediators are bioactive lipids which help regulate inflammation. We aimed to develop an ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method to quantify 58 pro-inflammatory and pro-resolving lipid mediators in plasma, determine preliminary reference ranges for adolescents, and investigate how total parenteral nutrition (TPN) containing omega-3 polyunsaturated fatty acid (n-3 PUFA) or n-6 PUFA based lipid emulsions influence lipid mediator concentrations in plasma. Methods Lipid mediators were extracted from plasma using SPE and measured using UHPLC-MS/MS. EDTA plasma was collected from healthy adolescents between 13 and 17 years of age to determine preliminary reference ranges and from mice given intravenous TPN for seven days containing either an n-3 PUFA or n-6 PUFA based lipid emulsion. Results We successfully quantified 43 lipid mediators in human plasma with good precision and recovery including several leukotrienes, prostaglandins, resolvins, protectins, maresins, and lipoxins. We found that the addition of methanol to human plasma after blood separation reduces post blood draw increases in 12-hydroxyeicosatetraenoic acid (12-HETE), 12-hydroxyeicosapentaenoic acid (12-HEPE), 12S-hydroxyeicosatrienoic acid (12S-HETrE), 14-hydroxydocosahexaenoic acid (14-HDHA) and thromboxane B2 (TXB2). Compared to the n-6 PUFA based TPN, the n-3 PUFA based TPN increased specialized pro-resolving mediators such as maresin 1 (MaR1), MaR2, protectin D1 (PD1), PDX, and resolvin D5 (RvD5), and decreased inflammatory lipid mediators such as leukotriene B4 (LTB4) and prostaglandin D2 (PGD2). Conclusions Our method provides an accurate and sensitive quantification of 58 lipid mediators from plasma samples, which we used to establish a preliminary reference range for lipid mediators in plasma samples of adolescents; and to show that n-3 PUFA, compared to n-6 PUFA rich TPN, leads to a less inflammatory lipid mediator profile in mice.

scholarly journals Suppression of chemotherapy-induced cytokine/lipid mediator surge and ovarian cancer by a dual COX-2/sEH inhibitor

2019 ◽  
Vol 116 (5) ◽  
pp. 1698-1703 ◽  
Author(s):  
Allison Gartung ◽  
Jun Yang ◽  
Vikas P. Sukhatme ◽  
Diane R. Bielenberg ◽  
Djanira Fernandes ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tumor Progression ◽  
Ovarian Tumor ◽  
Lipid Mediators ◽  
Lipid Mediator ◽  
Bioactive Lipids ◽  
First Line ◽  
Proinflammatory Mediators ◽  
Dual Inhibition ◽  
Cox 2

Although chemotherapy is a conventional cancer treatment, it may induce a protumorigenic microenvironment by triggering the release of proinflammatory mediators. In this study, we demonstrate that ovarian tumor cell debris generated by first-line platinum- and taxane-based chemotherapy accelerates tumor progression by stimulating a macrophage-derived “surge” of proinflammatory cytokines and bioactive lipids. Thus, targeting a single inflammatory mediator or pathway is unlikely to prevent therapy-induced tumor progression. Here, we show that combined pharmacological abrogation of the cyclooxygenase-2 (COX-2) and soluble epoxide hydrolase (sEH) pathways prevented the debris-induced surge of both cytokines and lipid mediators by macrophages. In animal models, the dual COX-2/sEH inhibitor PTUPB delayed the onset of debris-stimulated ovarian tumor growth and ascites leading to sustained survival over 120 days postinjection. Therefore, dual inhibition of COX-2/sEH may be an approach to suppress debris-stimulated ovarian tumor growth by preventing the therapy-induced surge of cytokines and lipid mediators.

scholarly journals Roles of multiple lipid mediators in stress and depression

2019 ◽  
Vol 31 (9) ◽  
pp. 579-587 ◽  
Author(s):  
Tomoyuki Furuyashiki ◽  
Satoshi Akiyama ◽  
Shiho Kitaoka
Keyword(s):  
Chronic Stress ◽  
Social Defeat ◽  
Lipid Mediators ◽  
Mental Illnesses ◽  
Lipid Mediator ◽  
Receptor Subtype ◽  
Social Defeat Stress ◽  
Beneficial Effects ◽  
Prostaglandin Synthase ◽  
Depressive Patients

AbstractProlonged or excessive stress may induce emotional and cognitive disturbances, and is a risk factor for mental illnesses. Using rodent chronic stress models of depression, roles of multiple lipid mediators related to inflammation have been revealed in chronic stress-induced emotional alterations. Prostaglandin (PG) E2, an arachidonic acid (AA)-derived lipid mediator, and its receptor subtype EP1 mediate depression-like behavior induced by repeated social defeat stress through attenuating prefrontal dopaminergic activity. Repeated social defeat stress activates microglia through innate immune receptors, and induces PGE2 synthesis through cyclooxygenase-1, a prostaglandin synthase enriched in microglia. PGD2, another AA-derived lipid mediator, has been implicated in depression induced by chronic stress, although either pro-depressive or anti-depressive actions have been reported. Chronic stress up-regulates hippocampal expression of 5-lipoxygenase, hence synthesis of cysteinyl leukotrienes, thereby inducing depression through their receptors. Consistent with beneficial effects of n-3 fatty acids in the diet of depressive patients, resolvins—a novel class of pro-resolving lipid mediators—in the brain attenuate neuroinflammation-associated depression. These findings in animal models of depression offer lipid mediators and related molecules as novel therapeutic targets for treating depression. To translate these findings into clinics, translational biomarkers to visualize lipid mediator profiles in depressive patients need to be established.

Divergent Lipid Mediator Profiles In Asthmatic And Healthy Subjects In Response To Diesel Exhaust Exposure

2012 ◽  
Author(s):  
Malin L. Nording ◽  
Susanna Lundstrom ◽  
Nirina Larsson ◽  
Maria Sehlstedt ◽  
Annelie F. Behndig ◽  
...  
Keyword(s):  
Diesel Exhaust ◽  
Healthy Subjects ◽  
Lipid Mediator ◽  
Diesel Exhaust Exposure

scholarly journals Lipid Mediator Informatics and Proteomics in Inflammation-Resolution

2006 ◽  
Vol 6 ◽  
pp. 589-614 ◽  
Author(s):  
Yan Lu ◽  
Song Hong ◽  
Katherine Gotlinger ◽  
Charles Serhan
Keyword(s):  
Mass Spectrometry ◽  
Peptide Mapping ◽  
Lipid Mediators ◽  
Automated System ◽  
Gas Chromatography Mass Spectrometry ◽  
Lipid Mediator ◽  
Enzyme Linked Immunosorbent Assay ◽  
Accurate Analysis ◽  
Spatial Production ◽  
Experimental Inflammation

Lipid mediator informatics is an emerging area denoted to the identification of bioactive lipid mediators (LMs) and their biosynthetic profiles and pathways. LM informatics and proteomics applied to inflammation, systems tissues research provides a powerful means of uncovering key biomarkers for novel processes in health and disease. By incorporating them with system biology analysis, we review here our initial steps toward elucidating relationships among a range of bimolecular classes and provide an appreciation of their roles and activities in the pathophysiology of disease. LM informatics employing liquid chromatography-ultraviolet-tandem mass spectrometry (LC-UV-MS/MS), gas chromatography-mass spectrometry (GC-MS), computer-based automated systems equipped with databases and novel searching algorithms, and enzyme-linked immunosorbent assay (ELISA) to evaluate and profile temporal and spatial production of mediators combined with proteomics at defined points during experimental inflammation and its resolution enable us to identify novel mediators in resolution. The automated system including databases and searching algorithms is crucial for prompt and accurate analysis of these lipid mediators biosynthesized from precursor polyunsaturated fatty acids such as eicosanoids, resolvins, and neuroprotectins, which play key roles in human physiology and many prevalent diseases, especially those related to inflammation. This review presents detailed protocols used in our lab for LM informatics and proteomics using LC-UV-MS/MS, GC-MS, ELISA, novel databases and searching algorithms, and 2-dimensional gel electrophoresis and LC-nanospray-MS/MS peptide mapping.

scholarly journals Immune-regulation and -functions of eicosanoid lipid mediators

2017 ◽  
Vol 398 (11) ◽  
pp. 1177-1191 ◽  
Author(s):  
Julia Esser-von Bieren
Keyword(s):  
Immune System ◽  
Immune Regulation ◽  
Current Knowledge ◽  
Feedback Regulation ◽  
Lipid Mediators ◽  
Target Cells ◽  
Bioactive Lipids ◽  
Physiological Processes ◽  
Immunoregulatory Cytokines ◽  
Infection And Inflammation

AbstractBioactive lipids regulate most physiological processes, from digestion to blood flow and from hemostasis to labor. Lipid mediators are also involved in multiple pathologies including cancer, autoimmunity or asthma. The pathological roles of lipid mediators are based on their intricate involvement in the immune system, which comprises source and target cells of these mediators. Based on their biosynthetic origin, bioactive lipids can be grouped into different classes [e.g. sphingolipids, formed from sphingosine or eicosanoids, formed from arachidonic acid (AA)]. Owing to the complexity of different mediator classes and the prominent immunological roles of eicosanoids, this review will focus solely on the immune-regulation of eicosanoids. Eicosanoids do not only control key immune responses (e.g. chemotaxis, antigen presentation, phagocytosis), but they are also subject to reciprocal control by the immune system. Particularly, key immunoregulatory cytokines such as IL-4 and IFN-γ shape the cellular eicosanoid profile, thus providing efficient feedback regulation between cytokine and eicosanoid networks. For the purpose of this review, I will first provide a short overview of the most important immunological functions of eicosanoids with a focus on prostaglandins (PGs) and leukotrienes (LTs). Second, I will summarize the current knowledge on immunological factors that regulate eicosanoid production during infection and inflammation.

scholarly journals New families of bioactive oxidized phospholipids generated by immune cells: identification and signaling actions

Blood ◽  
2012 ◽  
Vol 120 (10) ◽  
pp. 1985-1992 ◽  
Author(s):  
Valerie B. O'Donnell ◽  
Robert C. Murphy
Keyword(s):  
Immune Cells ◽  
Cell Biology ◽  
Cell Activation ◽  
Lipid Mediators ◽  
Innate Immune ◽  
Enzymatic Oxidation ◽  
Permeability Barrier ◽  
Bioactive Lipids ◽  
Membrane Phospholipids ◽  
Membrane Biology

Abstract Phospholipids are of critical importance in mammalian cell biology, both through providing a permeability barrier and acting as substrates for synthesis of lipid mediators. Recently, several new families of bioactive lipids were identified that form through the enzymatic oxidation of membrane phospholipids in circulating innate immune cells and platelets. These comprise eicosanoids attached to phosphatidylethanolamine and phosphatidylcholine and form within 2-5 minutes of cell activation by pathophysiologic agonists, via the coordinated action of receptors and enzymes. In this review, we summarize what is currently known regarding their structures, mechanisms of formation, cell biology, and signaling actions. We show that phospholipid oxidation by acutely activated immune cells is a controlled event, and we propose a central role in regulating membrane biology and innate immune function during health and disease. We also review the mass spectrometry methods used for identification of the lipids and describe how these approaches can be used for discovery of new lipid mediators in complex biologic samples.

scholarly journals Differential Lipid Mediator Involvement in the Different Forms of Genetic Frontotemporal Dementia: Novel Insights into Neuroinflammation

2021 ◽  
pp. 1-7
Author(s):  
Aitana Sogorb-Esteve ◽  
Romain A. Colas ◽  
Jesmond Dalli ◽  
Jonathan D. Rohrer
Keyword(s):  
Frontotemporal Dementia ◽  
Docosapentaenoic Acid ◽  
Lipid Mediators ◽  
Lipid Mediator ◽  
C9orf72 Expansion ◽  
Chromatography Tandem Mass Spectrometry ◽  
Liquid Chromatography Tandem Mass ◽  
Mapt Mutation ◽  
Homeostatic State

Background: The pathophysiology of frontotemporal dementia (FTD) is poorly understood but recent studies implicate neuroinflammation as an important factor. However, little is known so far about the role of the resolution pathway, the response to inflammation that allows tissue to return to a homeostatic state. Objective: We aimed to measure the concentrations of lipid mediators including specialized proresolving mediators (SPMs) and proinflammatory eicosanoids in the cerebrospinal fluid (CSF) of people with FTD. Methods: 15 people with genetic FTD (5 with C9orf72 expansions, 5 with GRN mutations, and 5 with MAPT mutations) were recruited to the study along with 15 age- and sex-matched healthy controls. Targeted liquid chromatography-tandem mass spectrometry techniques were used to measure the CSF concentrations of lipid mediators in the docosahexaenoic acid (DHA), n-3 docosapentaenoic acid, eicosapentaenoic acid, and arachidonic acid (AA) metabolomes. Results: Only the C9orf72 expansion carriers had higher concentrations of SPMs (DHA-derived maresins and DHA-derived resolvins) compared with controls. In contrast, GRN and MAPT mutation carriers had normal concentrations of SPMs but significantly higher concentrations of the proinflammatory AA-derived leukotrienes and AA-derived thromboxane compared with controls. Additionally, the C9orf72 expansion carriers also had significantly higher concentrations of AA-derived leukotrienes. Conclusion: This initial pilot study of lipid mediators provides a window into a novel biological pathway not previously investigated in FTD, showing differential patterns of alterations between those with C9orf72 expansions (where SPMs are higher) and GRN and MAPT mutations (where only proinflammatory eicosanoids are higher).

scholarly journals Reduced Plasma Lipid Mediators Are Directly Associated with Low Vitamin A Status in Women from Western Samar, Philippines

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 127-127
Author(s):  
Rodrigo Rosario ◽  
Reina Engle-Stone ◽  
Marjorie Haskell ◽  
Alex Brito ◽  
Karan Agrawal ◽  
...  
Keyword(s):  
Vitamin A ◽  
Multiple Reaction Monitoring ◽  
Plasma Lipid ◽  
Cross Sectional Study ◽  
Lipid Mediators ◽  
Lipid Mediator ◽  
Cross Sectional ◽  
Regulatory Effects ◽  
Plasma Retinol ◽  
Acquity Uplc

Abstract Objectives Vitamin A (VA) is an essential micronutrient that plays a key role in many biological processes, including growth, vision, immunity and reproduction. While evidence has been established to support these mechanisms, new studies suggest there may be more signaling compounds that are impacted by VA status. Lipid mediators, such as oxylipins and lysophospholipids, are signaling compounds that, in response to biological stimuli, exhibit regulatory effects on inflammation, immune function, vascular tone, and other systems. The objective was to investigate differences in lipid mediators associated with VA status. Methods In this cross-sectional study, blood samples from women in Western Samar, Philippines, were selected based on plasma retinol concentration indicating adequate (n = 5) or low (n = 5) VA status (retinol < 0.7 μmol/L). Retinol was measured using an Agilent 1200 HPLC-DAD. Oxylipin, endocannabinoid, bile acid, and lipidomics assays were analyzed on a Waters Acquity UPLC and detected using multiple reaction monitoring on a Sciex 4000 QTRAP. Data were adjusted for covariates related to the acute phase response, age, and BMI. Results Twenty-four lipid mediators were lower in the low VA status group (P < 0.05). These lipid mediators included the arachidonic acid-derived oxylipins’ lipoxin A4 and 6-trans-LTB4 formed via lipoxygenases (LOX), as well as the cyclooxygenase (COX) product PGD2. Several LOX and soluble epoxide hydrolase (sEH) oxylipins produced from eicosapentaenoic acid and the acylethanolamides LEA and PEA were lower (P < 0.05) in individuals with low plasma retinol levels. Numerous phospholipids and sphingolipids were also lower (P < 0.05) with decreased VA status, including two lysophosphatidylcholines, three lysophosphatidylethanolamines, two phosphatidylcholines, and two sphingomyelins. Conclusions In this exploratory study, VA status was directly associated with lipid mediator concentrations. Future studies testing the biological impact of lipid mediator changes with varying levels of VA status are necessary. Funding Sources NIH U24 DK097154, USDA Intramural Project 2032–51,530-022–00D, NIH T32-GM008799, Cal Poly CAFES SURP.

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