title: CD11c(+) monocyte/macrophages promote chronic Helicobacter hepaticus-induced intestinal inflammation through the production of IL-23.
abstract: In inflammatory bowel diseases, a breakdown in host microbial interactions accompanies sustained activation of immune cells in the gut. Functional studies suggest a key role for interleukin-23 (IL-23) in orchestrating intestinal inflammation. IL-23 can be produced by various mononuclear phagocytes (MNPs) following acute microbial stimulation, but little is known about the key cellular sources of IL-23 that drive chronic intestinal inflammation. Here we have addressed this question using a physiological model of bacteria-driven colitis. By combining conditional gene ablation and gene expression profiling, we found that IL-23 production by CD11c(+) MNPs was essential to trigger intestinal immunopathology and identified MHCII(+) monocytes and macrophages as the major source of IL-23. Expression of IL-23 by monocytes was acquired during their differentiation in the intestine and correlated with the expression of major histocompatibility complex class II (MHCII) and CD64. In contrast, Batf3-dependent CD103(+) CD11b(-) dendritic cells were dispensable for bacteria-induced colitis in this model. These studies reinforce the pathogenic role of monocytes in dysregulated responses to intestinal bacteria and identify production of IL-23 as a key component of this response. Further understanding of the functional sources of IL-23 in diverse forms of intestinal inflammation may lead to novel therapeutic strategies aimed at interrupting IL-23-driven immune pathology.
authors.affiliation: Translational Gastroenterology Unit, Experimental Medicine Division-NDM, University of Oxford, John Radcliffe Hospital, Oxford, UK.|Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
authors.forename: I C
authors.initials: IC
authors.lastname: Arnold
authors.affiliation: Translational Gastroenterology Unit, Experimental Medicine Division-NDM, University of Oxford, John Radcliffe Hospital, Oxford, UK.|Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.
authors.forename: S
authors.initials: S
authors.lastname: Mathisen
authors.affiliation: Translational Gastroenterology Unit, Experimental Medicine Division-NDM, University of Oxford, John Radcliffe Hospital, Oxford, UK.|Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
authors.forename: J
authors.initials: J
authors.lastname: Schulthess
authors.affiliation: Translational Gastroenterology Unit, Experimental Medicine Division-NDM, University of Oxford, John Radcliffe Hospital, Oxford, UK.|Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
authors.forename: C
authors.initials: C
authors.lastname: Danne
authors.affiliation: Translational Gastroenterology Unit, Experimental Medicine Division-NDM, University of Oxford, John Radcliffe Hospital, Oxford, UK.|Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
authors.forename: A N
authors.initials: AN
authors.lastname: Hegazy
authors.affiliation: Translational Gastroenterology Unit, Experimental Medicine Division-NDM, University of Oxford, John Radcliffe Hospital, Oxford, UK.|Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
authors.forename: F
authors.initials: F
authors.lastname: Powrie
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000276:immunology; D039521:CD11c Antigen / Q000235:genetics / Q000276:immunology*; D002908:Chronic Disease; D003092:Colitis / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D003106:Colon / Q000276:immunology / Q000473:pathology; D003713:Dendritic Cells / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D004847:Epithelial Cells / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D016481:Helicobacter Infections / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D044923:Helicobacter hepaticus / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology; D039001:Integrin alpha Chains / Q000235:genetics / Q000276:immunology; D053759:Interleukin-23 / Q000235:genetics / Q000276:immunology*; D007413:Intestinal Mucosa / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D037181:Lectins, C-Type / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009000:Monocytes / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction
chemical_list: D015703:Antigens, CD; D050976:Basic-Leucine Zipper Transcription Factors; D039521:CD11c Antigen; C529914:Clec9a protein, mouse; D000949:Histocompatibility Antigens Class II; D039001:Integrin alpha Chains; D053759:Interleukin-23; D037181:Lectins, C-Type; D017452:Receptors, IgG; D011971:Receptors, Immunologic; D012097:Repressor Proteins; C533289:SNFT protein, mouse; C091367:alpha E integrins