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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, CD / genetics
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Antigens, CD / immunology
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Basic-Leucine Zipper Transcription Factors / genetics
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Basic-Leucine Zipper Transcription Factors / immunology
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CD11c Antigen / genetics
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CD11c Antigen / immunology*
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Chronic Disease
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Colitis / genetics
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Colitis / immunology*
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Colitis / microbiology
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Colitis / pathology
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Colon / immunology
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Colon / pathology
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Dendritic Cells / immunology
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Dendritic Cells / microbiology
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Dendritic Cells / pathology
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Epithelial Cells / immunology
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Epithelial Cells / microbiology
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Epithelial Cells / pathology
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Gene Expression Profiling
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Gene Expression Regulation
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Helicobacter Infections / genetics
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Helicobacter Infections / immunology*
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Helicobacter Infections / microbiology
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Helicobacter Infections / pathology
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Helicobacter hepaticus / immunology
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Histocompatibility Antigens Class II / genetics
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Histocompatibility Antigens Class II / immunology
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Integrin alpha Chains / genetics
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Integrin alpha Chains / immunology
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Interleukin-23 / genetics
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Interleukin-23 / immunology*
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Intestinal Mucosa / immunology*
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Intestinal Mucosa / microbiology
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Intestinal Mucosa / pathology
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Lectins, C-Type / genetics
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Lectins, C-Type / immunology
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Macrophages / immunology*
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Macrophages / microbiology
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Macrophages / pathology
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Mice
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Mice, Transgenic
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Monocytes / immunology*
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Monocytes / microbiology
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Monocytes / pathology
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Receptors, IgG / genetics
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Receptors, IgG / immunology
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Receptors, Immunologic / genetics
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Receptors, Immunologic / immunology
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Repressor Proteins / genetics
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Repressor Proteins / immunology
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Signal Transduction
Substances
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Antigens, CD
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Basic-Leucine Zipper Transcription Factors
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CD11c Antigen
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Clec9a protein, mouse
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Histocompatibility Antigens Class II
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Integrin alpha Chains
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Interleukin-23
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Lectins, C-Type
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Receptors, IgG
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Receptors, Immunologic
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Repressor Proteins
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SNFT protein, mouse
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alpha E integrins