Abstract
Gut homeostasis and mucosal immune defense rely on the differential contributions of dendritic cells (DC) and macrophages. Here we show that colonic CX3CR1(+) mononuclear phagocytes are critical inducers of the innate response to Citrobacter rodentium infection. Specifically, the absence of IL-23 expression in macrophages or CD11b(+) DC results in the impairment of IL-22 production and in acute lethality. Highlighting immunopathology as a death cause, infected animals are rescued by the neutralization of IL-12 or IFNγ. Moreover, mice are also protected when the CD103(+) CD11b(-) DC compartment is rendered deficient for IL-12 production. We show that IL-12 production by colonic CD103(+) CD11b(-) DC is repressed by IL-23. Collectively, in addition to its role in inducing IL-22 production, macrophage-derived or CD103(-) CD11b(+) DC-derived IL-23 is required to negatively control the otherwise deleterious production of IL-12 by CD103(+) CD11b(-) DC. Impairment of this critical mononuclear phagocyte crosstalk results in the generation of IFNγ-producing former TH17 cells and fatal immunopathology.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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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CD11b Antigen / genetics
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CD11b Antigen / immunology
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CX3C Chemokine Receptor 1
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Citrobacter rodentium / immunology
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Citrobacter rodentium / pathogenicity*
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Colon / immunology*
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Colon / microbiology
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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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Enterobacteriaceae Infections / immunology*
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Enterobacteriaceae Infections / microbiology
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Enterobacteriaceae Infections / mortality
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Enterobacteriaceae Infections / pathology
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Gene Expression Regulation
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Homeostasis
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Immunity, Innate
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Immunity, Mucosal
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Integrin alpha Chains / genetics
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Integrin alpha Chains / immunology
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Interferon-gamma / genetics
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Interferon-gamma / immunology
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Interleukin-12 / genetics
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Interleukin-12 / immunology
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Interleukin-22
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Interleukin-23 / genetics
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Interleukin-23 / immunology*
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Interleukins / genetics
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Interleukins / 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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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, Chemokine / genetics
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Receptors, Chemokine / immunology
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Signal Transduction
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Survival Analysis
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Th17 Cells / immunology
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Th17 Cells / microbiology
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Th17 Cells / pathology
Substances
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Antigens, CD
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CD11b Antigen
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CX3C Chemokine Receptor 1
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CX3CR1 protein, human
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Integrin alpha Chains
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Interleukin-23
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Interleukins
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Receptors, Chemokine
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alpha E integrins
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Interleukin-12
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Interferon-gamma