title: Granulocyte Macrophage Colony-Stimulating Factor-Activated Eosinophils Promote Interleukin-23 Driven Chronic Colitis.
abstract: The role of intestinal eosinophils in immune homeostasis is enigmatic and the molecular signals that drive them from protective to tissue damaging are unknown. Most commonly associated with Th2 cell-mediated diseases, we describe a role for eosinophils as crucial effectors of the interleukin-23 (IL-23)-granulocyte macrophage colony-stimulating factor (GM-CSF) axis in colitis. Chronic intestinal inflammation was characterized by increased bone marrow eosinopoiesis and accumulation of activated intestinal eosinophils. IL-5 blockade or eosinophil depletion ameliorated colitis, implicating eosinophils in disease pathogenesis. GM-CSF was a potent activator of eosinophil effector functions and intestinal accumulation, and GM-CSF blockade inhibited chronic colitis. By contrast neutrophil accumulation was GM-CSF independent and dispensable for colitis. In addition to TNF secretion, release of eosinophil peroxidase promoted colitis identifying direct tissue-toxic mechanisms. Thus, eosinophils are key perpetrators of chronic inflammation and tissue damage in IL-23-mediated immune diseases and it suggests the GM-CSF-eosinophil axis as an attractive therapeutic target.
authors.affiliation: Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Roosevelt Drive, Oxford OX3 7FY, UK; Translational Gastroenterology Unit, Experimental Medicine Division Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors.forename: Thibault
authors.initials: T
authors.lastname: Griseri
authors.affiliation: Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Roosevelt Drive, Oxford OX3 7FY, UK; Translational Gastroenterology Unit, Experimental Medicine Division Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors.forename: Isabelle C
authors.initials: IC
authors.lastname: Arnold
authors.affiliation: Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Roosevelt Drive, Oxford OX3 7FY, UK; Translational Gastroenterology Unit, Experimental Medicine Division Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Pearson
authors.affiliation: Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Roosevelt Drive, Oxford OX3 7FY, UK; Translational Gastroenterology Unit, Experimental Medicine Division Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Krausgruber
authors.affiliation: Translational Gastroenterology Unit, Experimental Medicine Division Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Schiering
authors.affiliation: Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Roosevelt Drive, Oxford OX3 7FY, UK; Translational Gastroenterology Unit, Experimental Medicine Division Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors.forename: Fanny
authors.initials: F
authors.lastname: Franchini
authors.affiliation: Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Roosevelt Drive, Oxford OX3 7FY, UK; Translational Gastroenterology Unit, Experimental Medicine Division Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors.forename: Julie
authors.initials: J
authors.lastname: Schulthess
authors.affiliation: CSL Ltd. Research Department, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, 30 Flemington Road, Parkville, Victoria 3010, Australia.
authors.forename: Brent S
authors.initials: BS
authors.lastname: McKenzie
authors.affiliation: Division of Cell Signalling and Immunology, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Crocker
authors.affiliation: Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Roosevelt Drive, Oxford OX3 7FY, UK; Translational Gastroenterology Unit, Experimental Medicine Division Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK. Electronic address: fiona.powrie@kennedy.ox.ac.uk.
authors.forename: Fiona
authors.initials: F
authors.lastname: Powrie
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000276:immunology; D003092:Colitis / Q000276:immunology*; D053648:Cytokine Receptor Common beta Subunit / Q000235:genetics; D047209:Eosinophil Peroxidase / Q000378:metabolism; D004804:Eosinophils / Q000276:immunology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors / Q000276:immunology*; D007249:Inflammation / Q000276:immunology; D053760:Interleukin-23 Subunit p19 / Q000276:immunology*; D015848:Interleukin-5 / Q000037:antagonists & inhibitors; D007422:Intestines / Q000166:cytology / Q000276:immunology / Q000473:pathology; D047589:Leukocyte Reduction Procedures; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology; D048069:Tumor Necrosis Factors / Q000378:metabolism
chemical_list: D053648:Cytokine Receptor Common beta Subunit; C508841:Il23a protein, mouse; D053760:Interleukin-23 Subunit p19; D015848:Interleukin-5; D048069:Tumor Necrosis Factors; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D047209:Eosinophil Peroxidase