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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.

Original publication

DOI

10.1038/mi.2015.65

Type

Journal article

Journal

Mucosal immunology

Publication Date

03/2016

Volume

9

Pages

352 - 363

Addresses

Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.

Keywords

Intestinal Mucosa, Colon, Dendritic Cells, Monocytes, Macrophages, Epithelial Cells, Animals, Mice, Transgenic, Mice, Helicobacter hepaticus, Helicobacter Infections, Colitis, Chronic Disease, Lectins, C-Type, Receptors, Immunologic, Integrin alpha Chains, Antigens, CD11c, Receptors, IgG, Repressor Proteins, Antigens, CD, Histocompatibility Antigens Class II, Gene Expression Profiling, Signal Transduction, Gene Expression Regulation, Basic-Leucine Zipper Transcription Factors, Interleukin-23