title: Vagus nerve controls resolution and pro-resolving mediators of inflammation.
abstract: Resolution of inflammation is now recognized as a biosynthetically active process involving pro-resolving mediators. Here, we show in zymosan-initiated peritoneal inflammation that the vagus nerve regulates local expression of netrin-1, an axonal guidance molecule that activates resolution, and that vagotomy reduced local pro-resolving mediators, thereby delaying resolution. In netrin-1(+/-) mice, resolvin D1 (RvD1) was less effective in reducing neutrophil influx promoting resolution of peritonitis compared with Ntn1(+/+). Netrin-1 shortened the resolution interval, decreasing exudate neutrophils, reducing proinflammatory mediators, and stimulating the production of resolvins, protectins, and lipoxins. Human monocytes incubated with netrin-1 produced proresolving mediators, including resolvins and lipoxins. Netrin-1 and RvD1 displayed bidirectional activation in that they stimulated each other's expression and enhanced efferocytosis. These results indicate that the vagus nerve regulates both netrin-1 and pro-resolving lipid mediators, which act in a bidirectional fashion to stimulate resolution, and provide evidence for a novel mechanism for local neuronal control of resolution.
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 and Harvard Medical School, Boston, MA 02115 Clinic of Anesthesiology and Intensive Care Medicine, University Hospital Tübingen, Eberhard-Karls University, 72076 Tübingen, Germany.
authors.forename: Valbona
authors.initials: V
authors.lastname: Mirakaj
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 and Harvard Medical School, Boston, MA 02115.
authors.forename: Jesmond
authors.initials: J
authors.lastname: Dalli
authors.affiliation: Clinic of Anesthesiology and Intensive Care Medicine, University Hospital Tübingen, Eberhard-Karls University, 72076 Tübingen, Germany.
authors.forename: Tiago
authors.initials: T
authors.lastname: Granja
authors.affiliation: Clinic of Anesthesiology and Intensive Care Medicine, University Hospital Tübingen, Eberhard-Karls University, 72076 Tübingen, Germany cnserhan@zeus.bwh.harvard.edu peter.rosenberger@medizin.uni-tuebingen.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Rosenberger
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 and Harvard Medical School, Boston, MA 02115 cnserhan@zeus.bwh.harvard.edu peter.rosenberger@medizin.uni-tuebingen.de.
authors.forename: Charles N
authors.initials: CN
authors.lastname: Serhan
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects / Q000276:immunology; D004281:Docosahexaenoic Acids / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018836:Inflammation Mediators / Q000276:immunology* / Q000378:metabolism; D008055:Lipids / Q000737:chemistry / Q000276:immunology; D044045:Lipoxins / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D009414:Nerve Growth Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000075388:Netrin-1; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D010538:Peritonitis / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism; D011994:Recombinant Proteins / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014628:Vagotomy; D014630:Vagus Nerve / Q000276:immunology* / Q000378:metabolism / Q000601:surgery; D015054:Zymosan
chemical_list: D018836:Inflammation Mediators; D008055:Lipids; D044045:Lipoxins; C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; C000617353:Ntn1 protein, mouse; D011994:Recombinant Proteins; D025521:Tumor Suppressor Proteins; C518399:resolvin D1; D000075388:Netrin-1; D004281:Docosahexaenoic Acids; D015054:Zymosan