title: Proresolving and cartilage-protective actions of resolvin D1 in inflammatory arthritis.
abstract: Rheumatoid arthritis (RA) is a debilitating disease characterized by persistent accumulation of leukocytes within the articular cavity and synovial tissue. Metabololipidomic profiling of arthritic joints from omega-3 supplemented mice identified elevated levels of specialized proresolving lipid mediators (SPM) including resolvin D1 (RvD1). Profiling of human RA synovial fluid revealed physiological levels of RvD1, which - once applied to human neutrophils - attenuated chemotaxis. These results prompted analyses of the antiarthritic properties of RvD1 in a model of murine inflammatory arthritis. The stable epimer 17R-RvD1 (100 ng/day) significantly attenuated arthritis severity, cachexia, hind-paw edema, and paw leukocyte infiltration and shortened the remission interval. Metabololipidomic profiling in arthritic joints revealed 17R-RvD1 significantly reduced PGE2biosynthesis, while increasing levels of protective SPM. Molecular analyses indicated that 17R-RvD1 enhanced expression of genes associated with cartilage matrix synthesis, and direct intraarticular treatment induced chondroprotection. Joint protective actions of 17R-RvD1 were abolished in RvD1 receptor-deficient mice termedALX/fpr2/3-/-. These investigations open new therapeutic avenues for inflammatory joint diseases, providing mechanistic substance for the benefits of omega-3 supplementation in RA.
authors.affiliation: William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, United Kingdom.
authors.forename: Lucy V
authors.initials: LV
authors.lastname: Norling
authors.affiliation: William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, United Kingdom.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Headland
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Harvard Institutes of Medicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital (BWH) and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jesmond
authors.initials: J
authors.lastname: Dalli
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Harvard Institutes of Medicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital (BWH) and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Hildur H
authors.initials: HH
authors.lastname: Arnardottir
authors.affiliation: William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, United Kingdom.
authors.forename: Oliver
authors.initials: O
authors.lastname: Haworth
authors.affiliation: William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, United Kingdom.
authors.forename: Hefin R
authors.initials: HR
authors.lastname: Jones
authors.affiliation: Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School, Shriners Hospital for Children, Boston, Massachusetts, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Irimia
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Harvard Institutes of Medicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital (BWH) and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Charles N
authors.initials: CN
authors.lastname: Serhan
authors.affiliation: William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, United Kingdom.
authors.forename: Mauro
authors.initials: M
authors.lastname: Perretti