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Charles N Serhan - One of the best experts on this subject based on the ideXlab platform.
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A New E-Series Resolvin: RvE4 Stereochemistry and Function in Efferocytosis of Inflammation-Resolution
Frontiers in immunology, 2021Co-Authors: Stephania Libreros, Ashley E. Shay, Robert Nshimiyimana, David Fichtner, Michael J. Martin, Nicholas Wourms, Charles N SerhanAbstract:The resolution of the acute inflammatory response is governed by phagocytes actively clearing apoptotic cells and pathogens. Biosynthesis of the specialized pro-Resolving mediators (SPMs) is pivotal in the resolution of inflammation via their roles in innate immune cells . Resolvin E4 (RvE4: 5S,15S-dihydroxy-eicosapentaenoic acid) is a newly uncovered member of the E-series Resolvins biosynthesized from eicosapentaenoic acid (EPA) recently elucidated in physiologic hypoxia (Norris et al., 2019) . This new Resolvin was termed RvE4 given its ability to increase efferocytosis of apoptotic cells by macrophages. Herein, we report on the total organic synthesis of RvE4 confirming its unique structure, complete stereochemistry assignment and function. This synthetic RvE4 matched the physical properties of biogenic RvE4 material, i.e. ultra-violet (UV) absorbance, chromatographic behavior, and tandem mass spectrometry (MS2) fragmentation, as well as bioactivity. We confirmed RvE4 potent responses with human M2 macrophage efferocytosis of human apoptotic neutrophils and senescent red blood cells. Together, these results provide direct evidence for the assignment of the complete stereochemistry of RvE4 as 5S,15S-dihydroxy-6E,8Z,11Z,13E,17Z-eicosapentaenoic acid and its bioactions in human phagocyte response.
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Stereoselective Synthesis and Structural Confirmation of the Specialized Pro-Resolving Mediator Resolvin E4.
The Journal of organic chemistry, 2021Co-Authors: Amalie Føreid Reinertsen, Charles N Serhan, Ashley E. Shay, Trond Vidar Hansen, Karoline Gangestad Primdahl, Marius AursnesAbstract:Herein, we report the stereoselective and convergent synthesis of Resolvin E4, a newly identified specialized pro-Resolving mediator. This synthesis proves the absolute configuration and exact olefin geometry. Key elements of the successful strategy include a highly stereoselective MacMillan organocatalytic oxyamination, a Midland Alpine borane reduction, and the use of a 1,4-pentadiyne unit as a linchpin building block. The application of reaction telescoping in several of the synthetic transformations enabled the preparation of the Resolvin E4 methyl ester in 10% yield over 10 steps (longest linear sequence). The physical property (UV-Vis and LC-MS/MS) data of synthetic Resolvin E4 matched those obtained from biologically produced material.
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Identification of Chemotype Agonists for Human Resolvin D1 Receptor DRV1 with Pro-Resolving Functions.
Cell chemical biology, 2018Co-Authors: Nan Chiang, Elena Barnaeva, Juan J. Marugan, Noel Southall, Marc Ferrer, Charles N SerhanAbstract:Summary Resolution of acute inflammation is governed, in part, by specialized pro-Resolving mediators, including lipoxins, Resolvins, protectins, and maresins. Among them, Resolvin D1 (RvD1) exhibits potent pro-Resolving functions via activating human Resolvin D1 receptor (DRV1/GPR32). RvD1 is a complex molecule that requires challenging organic synthesis, diminishing its potential as a therapeutic. Therefore, we implemented a high-throughput screening of small-molecule libraries and identified several chemotypes that activated recombinant DRV1, represented by NCGC00120943 (C1A), NCGC00135472 (C2A), pMPPF, and pMPPI. These chemotypes also elicited rapid impedance changes in cells overexpressing recombinant DRV1. With human macrophages, they each stimulated phagocytosis of serum-treated zymosan at concentrations comparable with that of RvD1, the endogenous DRV1 ligand. In addition, macrophage phagocytosis of live E. coli was significantly increased by these chemotypes in DRV1-transfected macrophages, compared with mock-transfected cells. Taken together, these chemotypes identified by unbiased screens act as RvD1 mimetics, exhibiting pro-Resolving functions via interacting with human DRV1.
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Resolvin d3 multi level proResolving actions are host protective during infection
Prostaglandins Leukotrienes and Essential Fatty Acids, 2018Co-Authors: Paul C Norris, Julia M. Sanger, Hildur Arnardottir, David Fichtner, Gregory S Keyes, Charles N SerhanAbstract:Abstract Resolution of infection and inflammation is governed by innate immune cells. The Resolvin family of n-3 mediators produced by Resolving exudates stimulates clearance of neutrophils and attenuates pro-inflammatory signals. Using metabololipidomics, endogenous Resolvin D3 (RvD3) was identified in self-Resolving exudates during active E. coli infection. Through a new, independent synthetic route for RvD3, we matched endogenous and synthetic RvD3 and determined that RvD3 (ng doses) potently reduced the resolution interval ( R i ) by ~4.5h during E. coli peritonitis after administration at peak inflammation ( T max =12h) and increased leukocyte phagocytosis of E. coli and neutrophils as well as reduced proinflammatory cytokines, chemokines, MMP-2 and MMP-9. At pM-nM concentrations, RvD3 also enhanced human macrophage efferocytosis and bacterial phagocytosis, increased neutrophil bacterial phagocytosis and intracellular ROS generation, and reduced human platelet-PMN aggregation. These results provide additional evidence for potent RvD3 immunoresolvent actions in host defense, host protection and antimicrobial defense.
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Biosynthesis of D-Series Resolvins in Skin Provides Insights into their Role in Tissue Repair.
The Journal of investigative dermatology, 2018Co-Authors: Jason Hellmann, Charles N Serhan, Nan Chiang, Brian E Sansbury, Blenda Wong, Mansher Singh, Kristo Nuutila, Elof Eriksson, Matthew SpiteAbstract:Cutaneous injury causes underlying tissue damage that must be quickly repaired to minimize exposure to pathogens and to restore barrier function. While the role of growth factors in tissue repair is established, the role of lipid mediators in skin repair has not been investigated extensively. Using a mass spectrometry-based lipid mediator metabolomics approach, we identified D-series Resolvins and related pro-Resolving lipid mediators during skin injury in mice and pigs. Differentiation of human epidermal keratinocytes increased expression of 15-lipoxygenase and stereospecific production of 17S-hydroxydocosahexaenoic acid, the common upstream biosynthetic marker and precursor of D-series Resolvins. In human and pig skin, specific receptors for D-series Resolvins were expressed in the epidermal layer and mice deficient in RvD1 receptor Alx/Fpr2 showed an endogenous defect in re-epithelialization. Topical application of D-series Resolvins expedited re-epithelialization during skin injury and they enhanced migration of human epidermal keratinocytes in a receptor-dependent manner. The enhancement of re-epithelialization by RvD2 was lost in mice genetically deficient in its receptor and migration of keratinocytes stimulated with RvD2 was associated with activation of the PI3K-AKT-mTOR-S6 pathway, blockade of which prevented its pro-migratory actions. Collectively, these results demonstrate that Resolvins have direct roles in the tissue repair program.
Nan Chiang - One of the best experts on this subject based on the ideXlab platform.
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Identification of Chemotype Agonists for Human Resolvin D1 Receptor DRV1 with Pro-Resolving Functions.
Cell chemical biology, 2018Co-Authors: Nan Chiang, Elena Barnaeva, Juan J. Marugan, Noel Southall, Marc Ferrer, Charles N SerhanAbstract:Summary Resolution of acute inflammation is governed, in part, by specialized pro-Resolving mediators, including lipoxins, Resolvins, protectins, and maresins. Among them, Resolvin D1 (RvD1) exhibits potent pro-Resolving functions via activating human Resolvin D1 receptor (DRV1/GPR32). RvD1 is a complex molecule that requires challenging organic synthesis, diminishing its potential as a therapeutic. Therefore, we implemented a high-throughput screening of small-molecule libraries and identified several chemotypes that activated recombinant DRV1, represented by NCGC00120943 (C1A), NCGC00135472 (C2A), pMPPF, and pMPPI. These chemotypes also elicited rapid impedance changes in cells overexpressing recombinant DRV1. With human macrophages, they each stimulated phagocytosis of serum-treated zymosan at concentrations comparable with that of RvD1, the endogenous DRV1 ligand. In addition, macrophage phagocytosis of live E. coli was significantly increased by these chemotypes in DRV1-transfected macrophages, compared with mock-transfected cells. Taken together, these chemotypes identified by unbiased screens act as RvD1 mimetics, exhibiting pro-Resolving functions via interacting with human DRV1.
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Biosynthesis of D-Series Resolvins in Skin Provides Insights into their Role in Tissue Repair.
The Journal of investigative dermatology, 2018Co-Authors: Jason Hellmann, Charles N Serhan, Nan Chiang, Brian E Sansbury, Blenda Wong, Mansher Singh, Kristo Nuutila, Elof Eriksson, Matthew SpiteAbstract:Cutaneous injury causes underlying tissue damage that must be quickly repaired to minimize exposure to pathogens and to restore barrier function. While the role of growth factors in tissue repair is established, the role of lipid mediators in skin repair has not been investigated extensively. Using a mass spectrometry-based lipid mediator metabolomics approach, we identified D-series Resolvins and related pro-Resolving lipid mediators during skin injury in mice and pigs. Differentiation of human epidermal keratinocytes increased expression of 15-lipoxygenase and stereospecific production of 17S-hydroxydocosahexaenoic acid, the common upstream biosynthetic marker and precursor of D-series Resolvins. In human and pig skin, specific receptors for D-series Resolvins were expressed in the epidermal layer and mice deficient in RvD1 receptor Alx/Fpr2 showed an endogenous defect in re-epithelialization. Topical application of D-series Resolvins expedited re-epithelialization during skin injury and they enhanced migration of human epidermal keratinocytes in a receptor-dependent manner. The enhancement of re-epithelialization by RvD2 was lost in mice genetically deficient in its receptor and migration of keratinocytes stimulated with RvD2 was associated with activation of the PI3K-AKT-mTOR-S6 pathway, blockade of which prevented its pro-migratory actions. Collectively, these results demonstrate that Resolvins have direct roles in the tissue repair program.
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Resolvin D4 stereoassignment and its novel actions in host protection and bacterial clearance.
Scientific reports, 2016Co-Authors: Jeremy W. Winkler, Jesmond Dalli, Nan Chiang, Sarah K. Orr, Chien-yee C. Cheng, Julia M. Sanger, Nicos A. Petasis, Charles N SerhanAbstract:Resolvins of the D-series are specialized pro-Resolving lipid mediators that regulate cellular response by orchestrating resolution networks involved in host responses to injury and infection. Here, endogenous Resolvin D4 was identified in human tissues and found to persist late into the resolution phase of acute murine Staphylococcus aureus infections. Completion of the first total synthesis of Resolvin D4 established the absolute stereochemical configuration of RvD4 confirmed by matching with endogenous RvD4 from Resolving exudates in dorsal pouch S. aureus infections. In vivo, RvD4 (ng/mouse) reduced neutrophilic infiltration (~40%) and enhanced uptake of apoptotic PMN (51%) by human dermal fibroblasts at concentrations as low as 0.1 nM. These results establish the complete stereochemistry of RvD4 as 4S,5R,17S-trihydroxydocosa-6E,8E,10Z,13Z,15E,19Z-hexaenoic acid and its novel pro-Resolving actions in S. aureus infections as well as its potent ability to stimulate clearance of apoptotic cells by skin fibroblasts.
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Resolvin D1 and Aspirin-Triggered Resolvin D1 Regulate Histamine-stimulated Conjunctival Goblet Cell Secretion
Mucosal immunology, 2013Co-Authors: Robin R. Hodges, Charles N Serhan, Nan Chiang, Jianwei Jiao, Richard B. Carozza, Marie A. Shatos, Darlene A. DarttAbstract:Resolution of inflammation is an active process mediated by pro-resolution lipid mediators. As Resolvin (Rv) D1 is produced in the cornea, pro-resolution mediators could be effective in regulating inflammatory responses to histamine in allergic conjunctivitis. Two key mediators of resolution are the D-series Resolvins RvD1 or aspirin-triggered RvD1 (AT-RvD1). We used cultured conjunctival goblet cells to determine whether histamine actions can be terminated during allergic responses. We found cross-talk between two types of G protein-coupled receptors (GPRs), as RvD1 interacts with its receptor GPR32 to block histamine-stimulated H1 receptor increases in intracellular [Ca(2+)] ([Ca(2+)]i) preventing H1 receptor-mediated responses. In human and rat conjunctival goblet cells, RvD1 and AT-RvD1 each block histamine-stimulated secretion by preventing its increase in [Ca(2+)]i and activation of extracellular regulated-protein kinase (ERK)1/2. We suggest that D-series Resolvins regulate histamine responses in the eye and offer new treatment approaches for allergic conjunctivitis or other histamine-dependent pathologies.
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Resolvin D3 and Aspirin-Triggered Resolvin D3 Are Potent Immunoresolvents
Chemistry & biology, 2013Co-Authors: Jesmond Dalli, Nan Chiang, Jeremy W. Winkler, Chien-yee C. Cheng, Nicos A. Petasis, Romain A. Colas, Hildur Arnardottir, Charles N SerhanAbstract:Resolvins are a family of n-3 lipid mediators initially identified in Resolving inflammatory exudates that temper inflammatory responses to promote catabasis. Here, temporal metabololipidomics with self-limited Resolving exudates revealed that Resolvin (Rv) D3 has a distinct time frame from other lipid mediators, appearing late in the resolution phase. Using synthetic materials prepared by stereocontrolled total organic synthesis and metabololipidomics, we established complete stereochemistry of RvD3 and its aspirin-triggered 17R-epimer (AT-RvD3). Both synthetic Resolvins potently regulated neutrophils and mediators, reducing murine peritonitis and dermal inflammation. RvD3 and AT-RvD3 displayed leukocyte-directed actions, e.g., blocking human neutrophil transmigration and enhancing macrophage phagocytosis and efferocytosis. These results position RvD3 uniquely within the inflammation-resolution time frame to vantage and contribute to the beneficial actions of aspirin and essential n-3 fatty acids.
Ana M. Valdes - One of the best experts on this subject based on the ideXlab platform.
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Association of the Resolvin precursor 17-HDHA, but not D- or E- series Resolvins, with heat pain sensitivity and osteoarthritis pain in humans.
Scientific reports, 2017Co-Authors: Ana M. Valdes, Srinivasarao Ravipati, Cristina Menni, Abhishek Abhishek, Sarah Metrustry, Juliette Harris, Ayrun Nessa, Frances M K Williams, Tim D. Spector, Michael DohertyAbstract:Resolvins are omega-3 fatty acid derived potent bioactive lipids that resolve inflammation and modulate transient receptor potential channels. Exogenous administration of the Resolvin precursor 17-HDHA shows a strong analgesic effect in animal models of osteoarthritis and acute inflammatory pain, but has not been studied in humans. Our aim was to assess the role of 17-HDHA and Resolvins in heat pain sensitivity and in osteoarthritis pain in humans. Resolvins D1, D2, D3, D5, E1 and 17-HDHA, were measured by liquid chromatography-mass spectrometry and tested for association with heat pain thresholds in 250 healthy volunteers who had undergone quantitative sensory testing. Resolvins D1, D2 and 17-HDHA were then tested in 62 individuals affected with knee osteoarthritis and 52 age matched controls and tested for association with knee pain. Circulating levels of docosahexaenoic acid (DHA) were also measured. Levels of 17-HDHA, but not those of the other 5 Resolvins tested, were associated with increased heat pain thresholds (beta = 0.075; 95% CI 0.024, 0.126; p
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association of the Resolvin precursor 17 hdha but not d or e series Resolvins with heat pain sensitivity and osteoarthritis pain in humans
Scientific Reports, 2017Co-Authors: Ana M. Valdes, Srinivasarao Ravipati, Cristina Menni, Abhishek Abhishek, Sarah Metrustry, Juliette Harris, Ayrun Nessa, Frances M K WilliamsAbstract:Resolvins are omega-3 fatty acid derived potent bioactive lipids that resolve inflammation and modulate transient receptor potential channels. Exogenous administration of the Resolvin precursor 17-HDHA shows a strong analgesic effect in animal models of osteoarthritis and acute inflammatory pain, but has not been studied in humans. Our aim was to assess the role of 17-HDHA and Resolvins in heat pain sensitivity and in osteoarthritis pain in humans. Resolvins D1, D2, D3, D5, E1 and 17-HDHA, were measured by liquid chromatography-mass spectrometry and tested for association with heat pain thresholds in 250 healthy volunteers who had undergone quantitative sensory testing. Resolvins D1, D2 and 17-HDHA were then tested in 62 individuals affected with knee osteoarthritis and 52 age matched controls and tested for association with knee pain. Circulating levels of docosahexaenoic acid (DHA) were also measured. Levels of 17-HDHA, but not those of the other 5 Resolvins tested, were associated with increased heat pain thresholds (beta = 0.075; 95% CI 0.024, 0.126; p < 0.0046). 17-HDHA was associated with lower pain scores in OA patients (beta −0.41; 95% CI-0.69, −0.12; p < 0.005; adjusted for covariates) but not with radiographic osteoarthritis. The associations of 17-HDHA with heat pain sensitivity and osteoarthritis pain were independent of DHA levels.
Nicos A. Petasis - One of the best experts on this subject based on the ideXlab platform.
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Resolvin D4 stereoassignment and its novel actions in host protection and bacterial clearance.
Scientific reports, 2016Co-Authors: Jeremy W. Winkler, Jesmond Dalli, Nan Chiang, Sarah K. Orr, Chien-yee C. Cheng, Julia M. Sanger, Nicos A. Petasis, Charles N SerhanAbstract:Resolvins of the D-series are specialized pro-Resolving lipid mediators that regulate cellular response by orchestrating resolution networks involved in host responses to injury and infection. Here, endogenous Resolvin D4 was identified in human tissues and found to persist late into the resolution phase of acute murine Staphylococcus aureus infections. Completion of the first total synthesis of Resolvin D4 established the absolute stereochemical configuration of RvD4 confirmed by matching with endogenous RvD4 from Resolving exudates in dorsal pouch S. aureus infections. In vivo, RvD4 (ng/mouse) reduced neutrophilic infiltration (~40%) and enhanced uptake of apoptotic PMN (51%) by human dermal fibroblasts at concentrations as low as 0.1 nM. These results establish the complete stereochemistry of RvD4 as 4S,5R,17S-trihydroxydocosa-6E,8E,10Z,13Z,15E,19Z-hexaenoic acid and its novel pro-Resolving actions in S. aureus infections as well as its potent ability to stimulate clearance of apoptotic cells by skin fibroblasts.
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stereocontrolled total synthesis of the potent anti inflammatory and pro Resolving lipid mediator Resolvin d3 and its aspirin triggered 17r epimer
Organic Letters, 2013Co-Authors: Jeremy W. Winkler, Charles N Serhan, Jasim Uddin, Nicos A. PetasisAbstract:The first total synthesis of stereochemically pure Resolvin D3 and aspirin-triggered Resolvin D3 is reported. These enzymatic metabolites of docosahexaenoic acid (DHA) have potent anti-inflammatory and pro-Resolving actions. The convergent synthetic strategy is based on enantiomerically pure starting materials, and it is highly stereocontrolled.
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Resolvin D3 and Aspirin-Triggered Resolvin D3 Are Potent Immunoresolvents
Chemistry & biology, 2013Co-Authors: Jesmond Dalli, Nan Chiang, Jeremy W. Winkler, Chien-yee C. Cheng, Nicos A. Petasis, Romain A. Colas, Hildur Arnardottir, Charles N SerhanAbstract:Resolvins are a family of n-3 lipid mediators initially identified in Resolving inflammatory exudates that temper inflammatory responses to promote catabasis. Here, temporal metabololipidomics with self-limited Resolving exudates revealed that Resolvin (Rv) D3 has a distinct time frame from other lipid mediators, appearing late in the resolution phase. Using synthetic materials prepared by stereocontrolled total organic synthesis and metabololipidomics, we established complete stereochemistry of RvD3 and its aspirin-triggered 17R-epimer (AT-RvD3). Both synthetic Resolvins potently regulated neutrophils and mediators, reducing murine peritonitis and dermal inflammation. RvD3 and AT-RvD3 displayed leukocyte-directed actions, e.g., blocking human neutrophil transmigration and enhancing macrophage phagocytosis and efferocytosis. These results position RvD3 uniquely within the inflammation-resolution time frame to vantage and contribute to the beneficial actions of aspirin and essential n-3 fatty acids.
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Resolvin d1 binds human phagocytes with evidence for proResolving receptors
Proceedings of the National Academy of Sciences of the United States of America, 2010Co-Authors: Sriram Krishnamoorthy, Nan Chiang, Rong Yang, Antonio Recchiuti, Nicos A. Petasis, Stephanie Yacoubian, Chihhao Lee, Charles N SerhanAbstract:Endogenous mechanisms that act in the resolution of acute inflammation are essential for host defense and the return to homeostasis. Resolvin D1 (RvD1), biosynthesized during resolution, displays potent and stereoselective anti-inflammatory actions, such as limiting neutrophil infiltration and proResolving actions. Here, we demonstrate that RvD1 actions on human polymorphonuclear leukocytes (PMNs) are pertussis toxin sensitive, decrease actin polymerization, and block LTB4-regulated adhesion molecules (β2 integrins). Synthetic [3H]-RvD1 was prepared, which revealed specific RvD1 recognition sites on human leukocytes. Screening systems to identify receptors for RvD1 gave two candidates—ALX, a lipoxin A4 receptor, and GPR32, an orphan—that were confirmed using a β-arrestin-based ligand receptor system. Nuclear receptors including retinoid X receptor-α and peroxisome proliferator-activated receptor-α, -δ, -γ were not activated by either Resolvin E1 or RvD1 at bioactive nanomolar concentrations. RvD1 enhanced macrophage phagocytosis of zymosan and apoptotic PMNs, which increased with overexpression of human ALX and GPR32 and decreased with selective knockdown of these G-protein-coupled receptors. Also, ALX and GPR32 surface expression in human monocytes was up-regulated by zymosan and granulocyte-monocyte–colony-stimulating factor. These results indicate that RvD1 specifically interacts with both ALX and GPR32 on phagocytes and suggest that each plays a role in Resolving acute inflammation.
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Resolvin d2 is a potent regulator of leukocytes and controls microbial sepsis
Nature, 2009Co-Authors: Matthew Spite, Rong Yang, Nicos A. Petasis, Lucy V Norling, Lisa Summers, Dianne Cooper, Roderick J Flower, Mauro Perretti, Charles N SerhanAbstract:A growing body of evidence indicates that resolution of acute inflammation is an active process. Resolvins are a new family of lipid mediators enzymatically generated within resolution networks that possess unique and specific functions to orchestrate catabasis, the phase in which disease declines. Resolvin D2 (RvD2) was originally identified in Resolving exudates, yet its individual contribution in resolution remained to be elucidated. Here, we establish RvD2's potent stereoselective actions in reducing excessive neutrophil trafficking to inflammatory loci. RvD2 decreased leukocyte-endothelial interactions in vivo by endothelial-dependent nitric oxide production, and by direct modulation of leukocyte adhesion receptor expression. In mice with microbial sepsis initiated by caecal ligation and puncture, RvD2 sharply decreased both local and systemic bacterial burden, excessive cytokine production and neutrophil recruitment, while increasing peritoneal mononuclear cells and macrophage phagocytosis. These multi-level pro-Resolving actions of RvD2 translate to increased survival from sepsis induced by caecal ligation and puncture and surgery. Together, these results identify RvD2 as a potent endogenous regulator of excessive inflammatory responses that acts via multiple cellular targets to stimulate resolution and preserve immune vigilance.
Jesmond Dalli - One of the best experts on this subject based on the ideXlab platform.
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Resolvin d3 is dysregulated in arthritis and reduces arthritic inflammation
Journal of Immunology, 2016Co-Authors: Hildur Arnardottir, Jesmond Dalli, Romain A. Colas, Lucy V Norling, Mauro Perretti, Charles N SerhanAbstract:Uncontrolled inflammation is a unifying component of many chronic inflammatory diseases, such as arthritis. Resolvins (Rvs) are a new family from the endogenous specialized proResolving mediators (SPMs) that actively stimulate resolution of inflammation. In this study, using lipid mediator metabololipidomics with murine joints we found a temporal regulation of endogenous SPMs during self-Resolving inflammatory arthritis. The SPMs present in self-Resolving arthritic joints include the D-series Rvs, for example, RvD1, RvD2, RvD3, and RvD4. Of note, RvD3 levels were reduced in inflamed joints from mice with delayed-Resolving arthritis when compared with self-Resolving inflammatory arthritis. RvD3 was also reduced in serum from rheumatoid arthritis patients compared with healthy controls. RvD3 administration reduced joint leukocytes as well as paw joint eicosanoids, clinical scores, and edema. Taken together, these findings provide evidence for dysregulated endogenous RvD3 levels in inflamed paw joints and its potent actions in reducing murine arthritis.
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Aspirin-triggered Resolvin D1 is produced during self-Resolving gram-negative bacterial pneumonia and regulates host immune responses for the resolution of lung inflammation
Mucosal Immunology, 2016Co-Authors: Rajaelie E Abdulnour, R A Colas, Ho Pan Sham, David N Douda, X Ai, Jesmond Dalli, Charles N Serhan, B D LevyAbstract:Bacterial pneumonia is a leading cause of morbidity and mortality worldwide. Host responses to contain infection and mitigate pathogen-mediated lung inflammation are critical for pneumonia resolution. Aspirin-triggered Resolvin D1 (AT-RvD1; 7 S ,8 R ,17 R -trihydroxy-4Z,9E,11E,13Z,15E,19Z-docosahexaenoic acid) is a lipid mediator (LM) that displays organ-protective actions in sterile lung inflammation, and regulates pathogen-initiated cellular responses. Here, in a self-Resolving murine model of Escherichia coli pneumonia, LM metabololipidomics performed on lungs obtained at baseline, 24, and 72 h after infection uncovered temporal regulation of endogenous AT-RvD1 production. Early treatment with exogenous AT-RvD1 (1 h post infection) enhanced clearance of E. coli and Pseudomonas aeruginosa in vivo, and lung macrophage phagocytosis of fluorescent bacterial particles ex vivo . Characterization of macrophage subsets in the alveolar compartment during pneumonia identified efferocytosis by infiltrating macrophages (CD11b^Hi CD11c^Low) and exudative macrophages (CD11b^Hi CD11c^Hi). AT-RvD1 increased efferocytosis by these cells ex vivo , and accelerated neutrophil clearance during pneumonia in vivo . These anti-bacterial and pro-Resolving actions of AT-RvD1 were additive to antibiotic therapy. Taken together, these findings suggest that the pro-Resolving actions of AT-RvD1 during pneumonia represent a novel host-directed therapeutic strategy to complement the current antibiotic-centered approach for combatting infections.
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ProResolving lipid mediators Resolvin D1, Resolvin D2, and maresin 1 are critical in modulating T cell responses
Science Translational Medicine, 2016Co-Authors: Valerio Chiurchiù, Jesmond Dalli, Alessandro Leuti, Anders Jacobsson, Luca Battistini, Mauro MaccarroneAbstract:Resolution of inflammation is a finely regulated process mediated by specialized proResolving lipid mediators (SPMs), including docosahexaenoic acid (DHA)–derived Resolvins and maresins. The immunomodulatory role of SPMs in adaptive immune cells is of interest. We report that D-series Resolvins (Resolvin D1 and Resolvin D2) and maresin 1 modulate adaptive immune responses in human peripheral blood lymphocytes. These lipid mediators reduce cytokine production by activated CD8 + T cells and CD4 + T helper 1 (T H 1) and T H 17 cells but do not modulate T cell inhibitory receptors or abrogate their capacity to proliferate. Moreover, these SPMs prevented naive CD4 + T cell differentiation into T H 1 and T H 17 by down-regulating their signature transcription factors, T-bet and Rorc, in a mechanism mediated by the GPR32 and ALX/FPR2 receptors; they concomitantly enhanced de novo generation and function of Foxp3 + regulatory T (T reg ) cells via the GPR32 receptor. These results were also supported in vivo in a mouse deficient for DHA synthesis (Elovl2 −/− ) that showed an increase in T H 1/T H 17 cells and a decrease in T reg cells compared to wild-type mice. Additionally, either DHA supplementation in Elovl2 −/− mice or in vivo administration of Resolvin D1 significantly reduced cytokine production upon specific stimulation of T cells. These findings demonstrate actions of specific SPMs on adaptive immunity and provide a new avenue for SPM-based approaches to modulate chronic inflammation.
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Resolvin D4 stereoassignment and its novel actions in host protection and bacterial clearance.
Scientific reports, 2016Co-Authors: Jeremy W. Winkler, Jesmond Dalli, Nan Chiang, Sarah K. Orr, Chien-yee C. Cheng, Julia M. Sanger, Nicos A. Petasis, Charles N SerhanAbstract:Resolvins of the D-series are specialized pro-Resolving lipid mediators that regulate cellular response by orchestrating resolution networks involved in host responses to injury and infection. Here, endogenous Resolvin D4 was identified in human tissues and found to persist late into the resolution phase of acute murine Staphylococcus aureus infections. Completion of the first total synthesis of Resolvin D4 established the absolute stereochemical configuration of RvD4 confirmed by matching with endogenous RvD4 from Resolving exudates in dorsal pouch S. aureus infections. In vivo, RvD4 (ng/mouse) reduced neutrophilic infiltration (~40%) and enhanced uptake of apoptotic PMN (51%) by human dermal fibroblasts at concentrations as low as 0.1 nM. These results establish the complete stereochemistry of RvD4 as 4S,5R,17S-trihydroxydocosa-6E,8E,10Z,13Z,15E,19Z-hexaenoic acid and its novel pro-Resolving actions in S. aureus infections as well as its potent ability to stimulate clearance of apoptotic cells by skin fibroblasts.
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novel proResolving and tissue regenerative Resolvin and protectin sulfido conjugated pathways
The FASEB Journal, 2015Co-Authors: Jesmond Dalli, Romain A. Colas, Paul C Norris, Sesquile Ramon, Charles N SerhanAbstract:Local mediators orchestrate the host response to both sterile and infectious challenge and resolution. Recent evidence demonstrates that maresin sulfido-conjugates actively resolve acute inflammation and promote tissue regeneration. In this report, we investigated self-limited infectious exudates for novel bioactive chemical signals in tissue regeneration and resolution. By use of spleens from Escherichia coli infected mice, self-Resolving infectious exudates, human spleens, and blood from patients with sepsis, we identified 2 new families of potent molecules. Characterization of their physical properties and isotope tracking demonstrated that the bioactive structures contained a docosahexaenoate backbone and sulfido-conjugated triene or tetraene double-bond systems. Activated human phagocytes converted 17-hydro(peroxy)-4Z,7Z,10Z,13Z,15E,19Z-docosahexaenoic acid to these bioactive molecules. Regeneration of injured planaria was accelerated with nanomolar amounts of 16-glutathionyl, 17-hydroxy-4Z,7Z,10,12,14,19Z-docosahexaenoic acid and 16-cysteinylglycinyl, 17-hydroxy-4Z,7Z,10,12,14,19Z-docosahexaenoic acid (Protectin sulfido-conjugates) or 8-glutathionyl, 7,17-dihydroxy-4Z,9,11,13Z,15E,19Z-docosahexaenoic acid and 8-cysteinylglycinyl, 7,17-dihydroxy-4Z,9,11,13Z,15E,19Z-docosahexaenoic acid (Resolvin sulfido-conjugates). Each protectin and Resolvin sulfido-conjugate dose dependently (0.1-10 nM) stimulated human macrophage bacterial phagocytosis, phagolysosomal acidification, and efferocytosis. Together, these results identify 2 novel pathways and provide evidence for structural elucidation of new resolution moduli. These Resolvin and protectin conjugates identified in mice and human infected tissues control host responses promoting catabasis.
