title: Signaling and Immunoresolving Actions of Resolvin D1 in Inflamed Human Visceral Adipose Tissue.
abstract: Persistent activation of the innate immune system greatly influences the risk for developing metabolic complications associated with obesity. In this study, we explored the therapeutic potential of the specialized proresolving mediator (SPM) resolvin D1 (RvD1) to actively promote the resolution of inflammation in human visceral adipose tissue from obese (Ob) patients. Using liquid chromatography-tandem mass spectrometry-based metabololipidomic analysis, we identified unbalanced production of SPMs (i.e., D- and E-series resolvins, protectin D1, maresin 1, and lipoxins) with respect to inflammatory lipid mediators (i.e., leukotriene B4and PGs) in omental adipose tissue from Ob patients. In parallel, high-throughput transcriptomic analysis revealed a unique signature in this tissue that was characterized by overactivation of the IL-10 signaling pathway. Incubation of inflamed Ob visceral adipose tissues and human macrophages with RvD1 limited excessive activation of the IL-10 pathway by reducing phosphorylation of STAT proteins. Of interest, RvD1 blocked STAT-1 and its target inflammatory genes (i.e., CXCL9), as well as persistent STAT3 activation, without affecting the IL-10 anti-inflammatory response characterized by inhibition of IL-6, IL-1β, IL-8, and TNF-α. Furthermore, RvD1 promoted resolution by enhancing expression of the IL-10 target gene heme oxygenase-1 by mechanisms dependent on p38 MAPK activity. Together, our data show that RvD1 can tailor the quantitative and qualitative responses of human inflamed adipose tissue to IL-10 and provide a mechanistic basis for the immunoresolving actions of RvD1 in this tissue. These findings may have potential therapeutic implications in obesity-related insulin resistance and other metabolic complications.
authors.affiliation: Department of Biochemistry and Molecular Genetics, Hospital Clínic, August Pi i Sunyer Biomedical Research Institute, Barcelona 08036, Spain; esther.titos@ciberehd.org jclaria@clinic.ub.es.|Biomedical Research Networking Center on Liver and Digestive Diseases, Barcelona 08036, Spain.
authors.forename: Esther
authors.identifier: 0000-0002-2543-2243
authors.initials: E
authors.lastname: Titos
authors.affiliation: Department of Biochemistry and Molecular Genetics, Hospital Clínic, August Pi i Sunyer Biomedical Research Institute, Barcelona 08036, Spain.
authors.forename: Bibiana
authors.initials: B
authors.lastname: Rius
authors.affiliation: Department of Biochemistry and Molecular Genetics, Hospital Clínic, August Pi i Sunyer Biomedical Research Institute, Barcelona 08036, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: López-Vicario
authors.affiliation: Department of Biochemistry and Molecular Genetics, Hospital Clínic, August Pi i Sunyer Biomedical Research Institute, Barcelona 08036, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Alcaraz-Quiles
authors.affiliation: Department of Biochemistry and Molecular Genetics, Hospital Clínic, August Pi i Sunyer Biomedical Research Institute, Barcelona 08036, Spain.
authors.forename: Verónica
authors.initials: V
authors.lastname: García-Alonso
authors.affiliation: Department of Biochemistry and Molecular Genetics, Hospital Clínic, August Pi i Sunyer Biomedical Research Institute, Barcelona 08036, Spain.
authors.forename: Aritz
authors.initials: A
authors.lastname: Lopategi
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115.
authors.forename: Jesmond
authors.initials: J
authors.lastname: Dalli
authors.affiliation: Biomedical Research Networking Center on Liver and Digestive Diseases, Barcelona 08036, Spain.
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Lozano
authors.affiliation: European Foundation for the Study of Chronic Liver Failure, Barcelona 08036, Spain.
authors.forename: Vicente
authors.initials: V
authors.lastname: Arroyo
authors.affiliation: Department of Gastrointestinal Surgery, Hospital Clínic, August Pi i Sunyer Biomedical Research Institute, Barcelona 08036, Spain; and.
authors.forename: Salvadora
authors.initials: S
authors.lastname: Delgado
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115.
authors.forename: Charles N
authors.identifier: 0000-0003-4627-8545
authors.initials: CN
authors.lastname: Serhan
authors.affiliation: Department of Biochemistry and Molecular Genetics, Hospital Clínic, August Pi i Sunyer Biomedical Research Institute, Barcelona 08036, Spain; esther.titos@ciberehd.org jclaria@clinic.ub.es.|Biomedical Research Networking Center on Liver and Digestive Diseases, Barcelona 08036, Spain.|Department of Biomedical Sciences, University of Barcelona, Barcelona 08036, Spain.
authors.forename: Joan
authors.identifier: 0000-0003-4333-7749
authors.initials: J
authors.lastname: Clària
mesh_terms: D002478:Cells, Cultured; D004281:Docosahexaenoic Acids / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D050152:Intra-Abdominal Fat / Q000276:immunology* / Q000473:pathology; D009765:Obesity / Q000276:immunology / Q000473:pathology / Q000601:surgery; D015398:Signal Transduction
chemical_list: C518399:resolvin D1; D004281:Docosahexaenoic Acids