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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 Immunol

Publication Date

03/2016

Volume

9

Pages

352 - 363

Keywords

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