DOCSLIB.ORG

Maresin 1 Promotes Inflammatory Resolution, Neuroprotection and Functional Neurological Recovery After Spinal Cord Injury

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

This Accepted Manuscript has not been copyedited and formatted. The final version may differ from this version. Research Articles: Development/Plasticity/Repair Maresin 1 promotes inflammatory resolution, neuroprotection and functional neurological recovery after spinal cord injury Isaac Francos Quijorna1, Eva Santos-Nogueira1, Karsten Gronert2, Aaron B. Sullivan2, Marcel A Kopp3, Benedikt Brommer3,4, Samuel David5, Jan M. Schwab3,6,7 and Ruben Lopez Vales1 1Departament de Biologia Cel·lular, Fisiologia i Immunologia, Institut de Neurociències, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Universitat Autònoma de Barcelona, 08193 Bellaterra, Catalonia Spain 2Vision Science Program, School of Optometry, University of California Berkeley, Berkeley, CA 94598, USA 3Spinal Cord Alliance Berlin (SCAB) and Department of Neurology and Experimental Neurology, Charité Campus Mitte, Clinical and Experimental Spinal Cord Injury Research Laboratory (Neuroparaplegiology), Charité-Universitätsmedizin Berlin, Berlin, Germany 4F.M. Kirby Neurobiology Center, Boston Children's Hospital, and Department of Neurology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA 5Centre for Research in Neuroscience, The Research Institute of the McGill University Health Centre, Montreal, Canada 6Department of Neurology, Spinal Cord Injury Division, The Neurological Institute, The Ohio State University, Wexner Medical Centre, Columbus, OH 43210, USA 7Department of Neuroscience and Center for Brain and Spinal Cord Repair, Department of Physical Medicine and Rehabilitation, The Neurological Institute, The Ohio State University, Wexner Medical Centre, Columbus, OH 43210, USA. DOI: 10.1523/JNEUROSCI.1395-17.2017 Received: 22 May 2017 Revised: 27 September 2017 Accepted: 1 October 2017 Published: 3 November 2017 Author contributions: I.F.Q., J.S., and R.L.-V. designed research; I.F.Q., E.S.-N., M.K., B.B., J.S., and R.L.-V. performed research; I.F.Q., K.G., A.S., M.K., B.B., and R.L.-V. analyzed data; S.D. and J.S. contributed unpublished reagents/analytic tools; S.D., J.S., and R.L.-V. wrote the paper. Conflict of Interest: The authors declare no competing financial interests. This work has been supported by grants from the Spanish Ministry of Economy and Competitiveness (SAF2010-17851; SAF2013-48431-R), International Foundation for Research in Paraplegia and by funds from the Fondo de Investigación Sanitaria of Spain (TERCEL and CIBERNED) to R.L-V. JMS received funding from the Wings for Life Spinal Cord Research Foundation, the Era-Net-NEURON Program of the European Union (SILENCE #01EW170A), NIDILRR (#90SI5020), and the W.E. Hunt & C.M. Curtis Endowment. KG received funding from the National Institutes of Health (EY026082). The authors IFQ, SD, JMS and RLV are inventors on a patent application filled by Universitat Autònoma de Barcelona (Maresins for use in the treatment of CNS injuries, PCT/IB2017/054398) Correspondence: Ruben Lopez Vales, PhD, Departament de Biologia Cel·lular, Fisiologia i Immunologia, Institut de Neurociències, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Universitat Autònoma de Barcelona, 08193 Bellaterra, Catalonia, Spain., Email: [email protected] or Jan M. Schwab, MD, PhD, The Neurological Institute, The Ohio State University - Wexner Medical Center, 395 W. 12th Ave, 7th Floor, Columbus, OH 43210, USA., Email: [email protected] Cite as: J. Neurosci ; 10.1523/JNEUROSCI.1395-17.2017 Alerts: Sign up at www.jneurosci.org/cgi/alerts to receive customized email alerts when the fully formatted version of this article is published. Accepted manuscripts are peer-reviewed but have not been through the copyediting, formatting, or proofreading process. Copyright © 2017 the authors 1 2 Maresin 1 promotes inflammatory resolution, neuroprotection and functional 3 neurological recovery after spinal cord injury 4 Isaac Francos Quijorna1, Eva Santos-Nogueira1 , Karsten Gronert2, Aaron B. Sullivan2 , 5 Marcel A Kopp3, Benedikt Brommer3,4, Samuel David5, Jan M. Schwab3,6,7, Ruben 6 Lopez Vales1. 7 1Departament de Biologia Cel·lular, Fisiologia i Immunologia, Institut de Neurociències, Centro de 8 Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Universitat 9 Autònoma de Barcelona, 08193 Bellaterra, Catalonia Spain, 10 2Vision Science Program, School of Optometry, University of California Berkeley, Berkeley, CA 94598, 11 USA, 12 3Spinal Cord Alliance Berlin (SCAB) and Department of Neurology and Experimental Neurology, 13 Charité Campus Mitte, Clinical and Experimental Spinal Cord Injury Research Laboratory 14 (Neuroparaplegiology), Charité-Universitätsmedizin Berlin, Berlin, Germany, 15 4F.M. Kirby Neurobiology Center, Boston Children's Hospital, and Department of Neurology, Harvard 16 Medical School, 300 Longwood Avenue, Boston, MA 02115, USA, 17 5Centre for Research in Neuroscience, The Research Institute of the McGill University Health Centre, 18 Montreal, Canada, 19 6Department of Neurology, Spinal Cord Injury Division, The Neurological Institute, The Ohio State 20 University, Wexner Medical Centre, Columbus, OH 43210, USA, 21 7Department of Neuroscience and Center for Brain and Spinal Cord Repair, Department of Physical 22 Medicine and Rehabilitation, The Neurological Institute, The Ohio State University, Wexner Medical 23 Centre, Columbus, OH 43210, USA. 24 25 Running title: Maresin 1 in spinal cord injury 26 27 Correspondence: 28 Ruben Lopez Vales, PhD 29 Departament de Biologia Cel·lular, Fisiologia i Immunologia, 30 Institut de Neurociències, Centro de Investigación Biomédica en Red sobre 31 Enfermedades Neurodegenerativas, Universitat Autònoma de Barcelona, 08193 32 Bellaterra, Catalonia, Spain. 33 Email: [email protected] 34 35 or 36 Jan M. Schwab, MD, PhD 37 The Neurological Institute, The Ohio State University - Wexner Medical Center 38 395 W. 12th Ave, 7th Floor, Columbus, OH 43210, USA. 39 Email: [email protected] 40 41 Number of pages 28; Words Abstract 249; Words Introduction: 636; Words 42 Discussion 1438: 43 Number of Figures: 8; Number of Tables: 1 1 44 45 ACKNOWLEDGMENTS 46 This work has been supported by grants from the Spanish Ministry of Economy and 47 Competitiveness (SAF2010-17851; SAF2013-48431-R), International Foundation for 48 Research in Paraplegia and by funds from the Fondo de Investigación Sanitaria of Spain 49 (TERCEL and CIBERNED) to R.L-V. JMS received funding from the Wings for Life 50 Spinal Cord Research Foundation, the Era-Net-NEURON Program of the European 51 Union (SILENCE #01EW170A) , NIDILRR (#90SI5020), and the W.E. Hunt & C.M. 52 Curtis Endowment. KG received funding from the National Institutes of Health 53 (EY026082). The authors IFQ, SD, JMS and RLV are inventors on a patent application 54 filled by Universitat Autònoma de Barcelona (Maresins for use in the treatment of CNS 55 injuries, PCT/IB2017/054398) 56 57 2 58 ABSTRACT 59 Resolution of inflammation is defective after spinal cord injury (SCI), which impairs 60 tissue integrity and remodelling, and leads to functional deficits. Effective treatments 61 for SCI are not currently available. Maresin 1 (MaR1) is a highly conserved specialized 62 pro-resolving mediators (SPM) hosting potent anti-inflammatory and pro-resolving 63 properties with potent tissue regenerative actions. Here, we provide evidence that the 64 inappropriate biosynthesis of SPM in the lesioned spinal cord hampers the resolution of 65 inflammation and leads to deleterious consequences on neurological outcome in adult 66 female mice. We report that after spinal cord contusion injury in adult female mice, the 67 biosynthesis of SPM is not induced in the lesion site up to 2 weeks post-injury. 68 Exogenous administration of MaR1, a highly conserved SPM, propagated inflammatory 69 resolution after SCI, as revealed by accelerated clearance of neutrophils and the 70 reduction in macrophage accumulation at the lesion site. In the search of mechanisms 71 underlying the pro-resolving actions of MaR1 in SCI, we found that this SPM facilitated 72 several hallmarks of resolution of inflammation, including reduction of pro- 73 inflammatory cytokines (CXCL1, CXCL2, CCL3, CCL4, IL6, CSF3), silencing of 74 major inflammatory intracellular signalling cascades (STAT1, STAT3, STAT5, p38, 75 ERK1/2), redirection of macrophage activation towards a pro-repair phenotype, and 76 increase of the phagocytic engulfment of neutrophils by macrophages. Interestingly, 77 MaR1 administration significantly improved locomotor recovery and mitigated 78 secondary injury progression in a clinical relevant model of SCI. These findings suggest 79 that pro-resolution namely immunoresolvent therapies would be a novel approach to 80 improve neurological recovery after acute spinal cord injury. 81 82 Keywords: Inflammation, lipid mediators, Maresin 1, Resolution, Spinal Cord Injury 83 84 SIGNIFICANT STATEMENT 85 Inflammation is a protective response to injury or infection. In order to result in tissue 86 homeostasis, inflammation has to resolve over time. Incomplete or delayed resolution 87 leads to detrimental effects, including propagated tissue damage and impaired would 88 healing, as it occurs after spinal cord injury. We report that inflammation after spinal 89 cord injury is dysregulated, in part, due to inappropriate synthesis of pro-resolving lipid 90 mediators. We demonstrate that the administration of the resolution agonist, referred to 3 91 as maresin 1, after spinal cord injury
Recommended publications
  • Eicosanoids in Carcinogenesis

    Eicosanoids in Carcinogenesis

    4open 2019, 2,9 © B.L.D.M. Brücher and I.S. Jamall, Published by EDP Sciences 2019 https://doi.org/10.1051/fopen/2018008 Special issue: Disruption of homeostasis-induced signaling and crosstalk in the carcinogenesis paradigm “Epistemology of the origin of cancer” Available online at: Guest Editor: Obul R. Bandapalli www.4open-sciences.org REVIEW ARTICLE Eicosanoids in carcinogenesis Björn L.D.M. Brücher1,2,3,*, Ijaz S. Jamall1,2,4 1 Theodor-Billroth-Academy®, Germany, USA 2 INCORE, International Consortium of Research Excellence of the Theodor-Billroth-Academy®, Germany, USA 3 Department of Surgery, Carl-Thiem-Klinikum, Cottbus, Germany 4 Risk-Based Decisions Inc., Sacramento, CA, USA Received 21 March 2018, Accepted 16 December 2018 Abstract- - Inflammation is the body’s reaction to pathogenic (biological or chemical) stimuli and covers a burgeoning list of compounds and pathways that act in concert to maintain the health of the organism. Eicosanoids and related fatty acid derivatives can be formed from arachidonic acid and other polyenoic fatty acids via the cyclooxygenase and lipoxygenase pathways generating a variety of pro- and anti-inflammatory mediators, such as prostaglandins, leukotrienes, lipoxins, resolvins and others. The cytochrome P450 pathway leads to the formation of hydroxy fatty acids, such as 20-hydroxyeicosatetraenoic acid, and epoxy eicosanoids. Free radical reactions induced by reactive oxygen and/or nitrogen free radical species lead to oxygenated lipids such as isoprostanes or isolevuglandins which also exhibit pro-inflammatory activities. Eicosanoids and their metabolites play fundamental endocrine, autocrine and paracrine roles in both physiological and pathological signaling in various diseases. These molecules induce various unsaturated fatty acid dependent signaling pathways that influence crosstalk, alter cell–cell interactions, and result in a wide spectrum of cellular dysfunctions including those of the tissue microenvironment.
  • A Novel Resolvin-Based Strategy for Limiting Acetaminophen Hepatotoxicity

    A Novel Resolvin-Based Strategy for Limiting Acetaminophen Hepatotoxicity

    A Novel Resolvin-Based Strategy for Limiting Acetaminophen Hepatotoxicity The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Patel, Suraj J, Jay Luther, Stefan Bohr, Arvin Iracheta-Vellve, Matthew Li, Kevin R King, Raymond T Chung, and Martin L Yarmush. 2016. “A Novel Resolvin-Based Strategy for Limiting Acetaminophen Hepatotoxicity.” Clinical and Translational Gastroenterology 7 (3): e153. doi:10.1038/ctg.2016.13. http://dx.doi.org/10.1038/ctg.2016.13. Published Version doi:10.1038/ctg.2016.13 Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:26860020 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA Citation: Clinical and Translational Gastroenterology (2016) 7, e153; doi:10.1038/ctg.2016.13 & 2016 the American College of Gastroenterology All rights reserved 2155-384X/16 www.nature.com/ctg A Novel Resolvin-Based Strategy for Limiting Acetaminophen Hepatotoxicity Suraj J. Patel, MD, PhD1,2,5, Jay Luther, MD3,5, Stefan Bohr, MD1, Arvin Iracheta-Vellve, BS1, Matthew Li, PhD1, Kevin R. King, MD, PhD1, Raymond T. Chung, MD3 and Martin L. Yarmush, MD, PhD1,2,4 OBJECTIVES: Acetaminophen (APAP)-induced hepatotoxicity is a major cause of morbidity and mortality. The current pharmacologic treatment for APAP hepatotoxicity, N-acetyl cysteine (NAC), targets the initial metabolite-driven injury but does not directly affect the host inflammatory response.
  • Download Product Insert (PDF)

    Download Product Insert (PDF)

    PRODUCT INFORMATION 17(R)-Resolvin D1 Item No. 13060 CAS Registry No.: 528583-91-7 Formal Name: 7S,8R,17R-trihydroxy- 4Z,9E,11E,13Z,15E19Z- HO docosahexaenoic acid Synonyms: Aspirin-triggered Resolvin D1, AT-RvD1, 17-epi-Resolvin D1, 17(R)-RvD1 COOH OH MF: C22H32O5 FW: 376.5 Purity: ≥95% Stability: ≥1 year at -80°C Supplied as: A solution in ethanol OH Special Conditions: Light Sensitive UV/Vis.: λmax: 302 nm Laboratory Procedures For long term storage, we suggest that 17(R)-resolvin D1 (17(R)-RvD1) be stored as supplied at -80°C. It should be stable for at least one year. 17(R)-RvD1 is supplied as a solution in ethanol. To change the solvent, simply evaporate the ethanol under a gentle stream of nitrogen and immediately add the solvent of choice. It is recommended that this product be stored and handled in an ethanol solution. Resolvins can isomerize and degrade when put into freeze thaw conditions and/or in solvents such as DMF or DMSO. Further dilutions of the stock solution into aqueous buffers or isotonic saline should be made prior to performing biological experiments. Ensure that the residual amount of organic solvent is insignificant, since organic solvents may have physiological effects at low concentrations. If an organic solvent-free solution of 17(R)-RvD1 is needed, it can be prepared by evaporating the ethanol and directly dissolving the neat oil in aqueous buffers. The solubility of 17(R)-RvD1 in PBS, pH 7.2, is approximately 0.05 mg/ml. Aqueous solutions of 17(R)-RvD1 should be discarded immediately after use.
  • Effects of Maresin 1, an Omega-3 Fatty Acid-Derived Lipid Mediator, on Adipose Tissue and Liver Function in Obesity [Tesis Docto

    Effects of Maresin 1, an Omega-3 Fatty Acid-Derived Lipid Mediator, on Adipose Tissue and Liver Function in Obesity [Tesis Docto

    Facultad de Farmacia y Nutrición Effects of Maresin 1, an omega-3 fatty acid-derived lipid mediator, on adipose tissue and liver function in obesity Efectos de Maresina 1, un mediador lipídico derivado de los ácidos grasos omega-3, en la función del tejido adiposo y el hígado en obesidad Laura Laiglesia González Pamplona, 2017 Facultad de Farmacia y Nutrición Memoria presentada por Dña. Laura Laiglesia González para aspirar al grado de Doctor por la Universidad de Navarra. Fdo. Laura Laiglesia González El presente trabajo ha sido realizado bajo nuestra dirección en el Departamento de Ciencias de la Alimentación y Fisiología de la Facultad de Farmacia y Nutrición de la Universidad de Navarra y autorizamos su presentación ante el Tribunal que lo ha de juzgar. VºBº Directora VºBº Co-Directora María Jesús Moreno Aliaga Silvia Lorente Cebrián Este trabajo ha sido posible gracias a la financiación de diversas entidades: Gobierno de España (Ministerio de Economía, Industria y Competitividad) [BFU2012-36089 y BFU2015-65937-R], Gobierno de Navarra (Departamento de Salud) [67-2015], Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERObn) Instituto de Salud Carlos III (ISCIII) [CB12/03/30002], Centro de Investigación en Nutrición (Universidad de Navarra). Beca predoctoral 2013-2017: La investigación que ha dado lugar a estos resultados ha sido impulsada por la Obra Social "la Caixa” y la Asociación de Amigos de la Universidad de Navarra. Acknowledgements Me gustaría expresar mi agradecimiento a esas personas que han hecho posible la realización de este trabajo durante los últimos cuatro años, hasta aquellos que me han escuchado a pesar de no entender muy bien que es lo que estaba haciendo.
  • Maresin 1 Biosynthesis During Platelet–Neutrophil Interactions Is Organ-Protective

    Maresin 1 Biosynthesis During Platelet–Neutrophil Interactions Is Organ-Protective

    Maresin 1 biosynthesis during platelet–neutrophil interactions is organ-protective Raja-Elie E. Abdulnoura,1, Jesmond Dallib,1, Jennifer K. Colbya, Nandini Krishnamoorthya, Jack Y. Timmonsa, Sook Hwa Tana, Romain A. Colasb, Nicos A. Petasisc, Charles N. Serhanb, and Bruce D. Levya,b,2 aPulmonary and Critical Care Medicine and bCenter for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115; and cDepartment of Chemistry, University of Southern California, Los Angeles, CA 90089 Edited by Derek William Gilroy, University College London, London, United Kingdom, and accepted by the Editorial Board October 10, 2014 (received for review April 17, 2014) Unregulated acute inflammation can lead to collateral tissue injury 12-lipoxygenase that may be capable of generating the 13S,14S- in vital organs, such as the lung during the acute respiratory distress epoxy-maresin intermediate and participating in MaR1 production syndrome. In response to tissue injury, circulating platelet–neutro- at sites of vascular inflammation. Here, we provide evidence for phil aggregates form to augment neutrophil tissue entry. These a MaR1 biosynthetic route during platelet–neutrophil interactions early cellular events in acute inflammation are pivotal to timely that is operative in vivo in a murine model of ARDS to restrain resolution by mechanisms that remain to be elucidated. Here, we inflammation and restore homeostasis of the injured lung. identified a previously undescribed biosynthetic route during hu- man platelet–neutrophil interactions for the proresolving mediator Results maresin 1 (MaR1; 7R,14S-dihydroxy-docosa-4Z,8E,10E,12Z,16Z,19Z- To determine if platelets can participate in vascular MaR1 bio- hexaenoic acid).
  • Therapeutic Effects of Specialized Pro-Resolving Lipids Mediators On

    Therapeutic Effects of Specialized Pro-Resolving Lipids Mediators On

    antioxidants Review Therapeutic Effects of Specialized Pro-Resolving Lipids Mediators on Cardiac Fibrosis via NRF2 Activation 1, 1,2, 2, Gyeoung Jin Kang y, Eun Ji Kim y and Chang Hoon Lee * 1 Lillehei Heart Institute, University of Minnesota, Minneapolis, MN 55455, USA; [email protected] (G.J.K.); [email protected] (E.J.K.) 2 College of Pharmacy, Dongguk University, Seoul 04620, Korea * Correspondence: [email protected]; Tel.: +82-31-961-5213 Equally contributed. y Received: 11 November 2020; Accepted: 9 December 2020; Published: 10 December 2020 Abstract: Heart disease is the number one mortality disease in the world. In particular, cardiac fibrosis is considered as a major factor causing myocardial infarction and heart failure. In particular, oxidative stress is a major cause of heart fibrosis. In order to control such oxidative stress, the importance of nuclear factor erythropoietin 2 related factor 2 (NRF2) has recently been highlighted. In this review, we will discuss the activation of NRF2 by docosahexanoic acid (DHA), eicosapentaenoic acid (EPA), and the specialized pro-resolving lipid mediators (SPMs) derived from polyunsaturated lipids, including DHA and EPA. Additionally, we will discuss their effects on cardiac fibrosis via NRF2 activation. Keywords: cardiac fibrosis; NRF2; lipoxins; resolvins; maresins; neuroprotectins 1. Introduction Cardiovascular disease is the leading cause of death worldwide [1]. Cardiac fibrosis is a major factor leading to the progression of myocardial infarction and heart failure [2]. Cardiac fibrosis is characterized by the net accumulation of extracellular matrix proteins in the cardiac stroma and ultimately impairs cardiac function [3]. Therefore, interest in substances with cardioprotective activity continues.
  • Novel Resolvin D2 Receptor Axis in Infectious Inflammation Nan Chiang, Xavier De La Rosa, Stephania Libreros and Charles N

    Novel Resolvin D2 Receptor Axis in Infectious Inflammation Nan Chiang, Xavier De La Rosa, Stephania Libreros and Charles N

    Novel Resolvin D2 Receptor Axis in Infectious Inflammation Nan Chiang, Xavier de la Rosa, Stephania Libreros and Charles N. Serhan This information is current as of September 25, 2021. J Immunol 2017; 198:842-851; Prepublished online 19 December 2016; doi: 10.4049/jimmunol.1601650 http://www.jimmunol.org/content/198/2/842 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2016/12/16/jimmunol.160165 Material 0.DCSupplemental References This article cites 51 articles, 19 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/198/2/842.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 25, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2017 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Novel Resolvin D2 Receptor Axis in Infectious Inflammation Nan Chiang,1 Xavier de la Rosa,1 Stephania Libreros, and Charles N. Serhan Resolution of acute inflammation is an active process governed by specialized proresolving mediators, including resolvin (Rv)D2, that activates a cell surface G protein–coupled receptor, GPR18/DRV2.
  • Association of the Resolvin Precursor 17-HDHA, but Not D- Or E

    Association of the Resolvin Precursor 17-HDHA, but Not D- Or E

    www.nature.com/scientificreports OPEN Association of the resolvin precursor 17-HDHA, but not D- or E- series resolvins, with heat pain Received: 10 March 2017 Accepted: 24 July 2017 sensitivity and osteoarthritis pain in Published: xx xx xxxx humans Ana M. Valdes1,2,3, Srinivasarao Ravipati4,6, Cristina Menni1, Abhishek Abhishek2, Sarah Metrustry1, Juliette Harris1, Ayrun Nessa1, Frances M. K. Williams1, Tim D. Spector1, Michael Doherty2, Victoria Chapman3,5,6 & David A. Barrett 4 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.
  • Omega-3 Fatty Acid-Derived Resolvin D2 Regulates Human Placental Vascular Smooth Muscle and Extravillous Trophoblast Activities

    Omega-3 Fatty Acid-Derived Resolvin D2 Regulates Human Placental Vascular Smooth Muscle and Extravillous Trophoblast Activities

    University of Nebraska - Lincoln DigitalCommons@University of Nebraska - Lincoln Nutrition and Health Sciences -- Faculty Publications Nutrition and Health Sciences, Department of 9-7-2019 Omega-3 Fatty Acid-Derived Resolvin D2 Regulates Human Placental Vascular Smooth Muscle and Extravillous Trophoblast Activities Arzu Ulu University of California, Riverside Prakash K. Sahoo University of Nebraska-Lincoln Ana G. Yuil-Valdes University of Nebraska Medical Center, [email protected] Maheswari Mukherjee University of Nebraska Medical Center, [email protected] Matthew Van Ormer University of Nebraska Medical Center, [email protected] Follow this and additional works at: https://digitalcommons.unl.edu/nutritionfacpub See P nextart of page the forHuman additional and Clinical authors Nutrition Commons, Molecular, Genetic, and Biochemical Nutrition Commons, and the Other Nutrition Commons Ulu, Arzu; Sahoo, Prakash K.; Yuil-Valdes, Ana G.; Mukherjee, Maheswari; Ormer, Matthew Van; Muthuraj, Philma Glora; Thompson, Maranda; Berry, Ann Anderson; Hanson, Corrine K.; Natarajan, Sathish Kumar; and Nordgren, Tara M., "Omega-3 Fatty Acid-Derived Resolvin D2 Regulates Human Placental Vascular Smooth Muscle and Extravillous Trophoblast Activities" (2019). Nutrition and Health Sciences -- Faculty Publications. 215. https://digitalcommons.unl.edu/nutritionfacpub/215 This Article is brought to you for free and open access by the Nutrition and Health Sciences, Department of at DigitalCommons@University of Nebraska - Lincoln. It has been accepted for inclusion in Nutrition and Health Sciences -- Faculty Publications by an authorized administrator of DigitalCommons@University of Nebraska - Lincoln. Authors Arzu Ulu, Prakash K. Sahoo, Ana G. Yuil-Valdes, Maheswari Mukherjee, Matthew Van Ormer, Philma Glora Muthuraj, Maranda Thompson, Ann Anderson Berry, Corrine K.
  • Maresin 1 Activates LGR6 Receptor Promoting Phagocyte Immunoresolvent Functions

    Maresin 1 Activates LGR6 Receptor Promoting Phagocyte Immunoresolvent Functions

    Maresin 1 activates LGR6 receptor promoting phagocyte immunoresolvent functions Nan Chiang, … , Xavier de la Rosa, Charles N. Serhan J Clin Invest. 2019;129(12):5294-5311. https://doi.org/10.1172/JCI129448. Research Article Inflammation Graphical abstract Find the latest version: https://jci.me/129448/pdf RESEARCH ARTICLE The Journal of Clinical Investigation Maresin 1 activates LGR6 receptor promoting phagocyte immunoresolvent functions Nan Chiang, Stephania Libreros, Paul C. Norris, Xavier de la Rosa, and Charles N. Serhan Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA. Resolution of acute inflammation is an active process orchestrated by endogenous mediators and mechanisms pivotal in host defense and homeostasis. The macrophage mediator in resolving inflammation, maresin 1 (MaR1), is a potent immunoresolvent, stimulating resolution of acute inflammation and organ protection. Using an unbiased screening of greater than 200 GPCRs, we identified MaR1 as a stereoselective activator for human leucine-rich repeat containing G protein–coupled receptor 6 (LGR6), expressed in phagocytes. MaR1 specificity for recombinant human LGR6 activation was established using reporter cells expressing LGR6 and functional impedance sensing. MaR1-specific binding to LGR6 was confirmed using 3H-labeled MaR1. With human and mouse phagocytes, MaR1 (0.01–10 nM) enhanced phagocytosis, efferocytosis, and phosphorylation of a panel of proteins including the ERK and cAMP response element-binding protein. These MaR1 actions were significantly amplified with LGR6 overexpression and diminished by gene silencing in phagocytes. Thus, we provide evidence for MaR1 as an endogenous activator of human LGR6 and a novel role of LGR6 in stimulating MaR1’s key proresolving functions of phagocytes.
  • 15-Epi-Lipoxin A4, Resolvin D2, and Resolvin D3 Induce NF-Κb

    15-Epi-Lipoxin A4, Resolvin D2, and Resolvin D3 Induce NF-Κb

    Published March 9, 2018, doi:10.4049/jimmunol.1602090 The Journal of Immunology 15-epi-Lipoxin A4, Resolvin D2, and Resolvin D3 Induce NF-kB Regulators in Bacterial Pneumonia Ho Pan Sham,*,1 Katherine H. Walker,*,1 Raja-Elie E. Abdulnour,* Nandini Krishnamoorthy,* David N. Douda,* Paul C. Norris,† Ioanna Barkas,* Sarah Benito-Figueroa,* Jennifer K. Colby,* Charles N. Serhan,† and Bruce D. Levy* Specialized proresolving mediators (SPMs) decrease NF-kB activity to prevent excessive tissue damage and promote the resolution of acute inflammation. Mechanisms for NF-kB regulation by SPMs remain to be determined. In this study, after LPS challenge, the SPMs 15-epi-lipoxin A4 (15-epi-LXA4), resolvin D1, resolvin D2, resolvin D3, and 17-epi-resolvin D1 were produced in vivo in murine lungs. In LPS-activated human bronchial epithelial cells, select SPMs increased expression of the NF-kB regulators A20 and single Ig IL-1R–related molecule (SIGIRR). Of interest, 15-epi-LXA4 induced A20 and SIGIRR in an lipoxin A4 receptor/ formyl peptide receptor 2 (ALX/FPR2) receptor–dependent manner in epithelial cells and in murine pneumonia. This SPM regulated NF-kB–induced cytokines to decrease pathogen-mediated inflammation. In addition to dampening lung inflammation, surprisingly, 15-epi-LXA4 also enhanced pathogen clearance with increased antimicrobial peptide expression. Taken together, to our knowledge these results are the first to identify endogenous agonists for A20 and SIGIRR expression to regulate NF-kB activity and to establish mechanisms for NF-kB regulation by SPMs for pneumonia resolution. The Journal of Immunology, 2018, 200: 000–000. athogen-induced inflammation is a major and untreated to bacteria, including generation of proinflammatory cytokines and source of morbidity and mortality in common infections, antimicrobial peptide production (8, 9).
  • Inhibition of Δ24-Dehydrocholesterol Reductase Activates Pro-Resolving Lipid Mediator Biosynthesis and Inflammation Resolution

    Inhibition of Δ24-Dehydrocholesterol Reductase Activates Pro-Resolving Lipid Mediator Biosynthesis and Inflammation Resolution

    Inhibition of Δ24-dehydrocholesterol reductase activates pro-resolving lipid mediator biosynthesis and inflammation resolution Andreas Körnera, Enchen Zhoub, Christoph Müllerc, Yassene Mohammedd, Sandra Hercegc, Franz Bracherc, Patrick C. N. Rensenb, Yanan Wangb, Valbona Mirakaja, and Martin Gierad,1 aDepartment of Anesthesiology and Intensive Care Medicine, Molecular Intensive Care Medicine, Eberhard Karls University Tübingen, 72072 Tübingen, Germany; bDepartment of Medicine, Division of Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, 2333ZA Leiden, The Netherlands; cDepartment of Pharmacy-Center for Drug Research, Ludwig Maximilians University Munich, 81377 Munich, Germany; and dCenter for Proteomics and Metabolomics, Leiden University Medical Center, 2333ZA Leiden, The Netherlands Edited by Christopher K. Glass, University of California San Diego, La Jolla, CA, and approved September 3, 2019 (received for review July 27, 2019) Targeting metabolism through bioactive key metabolites is an desmosterol to cholesterol (Fig. 1A). Of the 10 enzymes involved in upcoming future therapeutic strategy. We questioned how modi- distal cholesterol biosynthesis, starting with squalene, DHCR24 has fying intracellular lipid metabolism could be a possible means for recently taken center stage in several diseases. This enzyme has been alleviating inflammation. Using a recently developed chemical probe linked to Alzheimer’s disease (AD), oncogenic and oxidative stress (SH42), we inhibited distal cholesterol biosynthesis through selective (10), hepatitis C virus (HCV) infections (11), differentiation of T 24 inhibition of Δ -dehydrocholesterol reductase (DHCR24). Inhibition helper-17 cells (12), development of foam cells (13), and prostate of DHCR24 led to an antiinflammatory/proresolving phenotype in a cancer (14). While the role of DHCR24 in AD is controversially murine peritonitis model.