IL-23-mediated mononuclear phagocyte crosstalk protects mice from Citrobacter rodentium-induced colon immunopathology

Nat Commun. 2015 Mar 12;6:6525. doi: 10.1038/ncomms7525.

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

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antigens, CD / genetics
  • Antigens, CD / immunology
  • CD11b Antigen / genetics
  • CD11b Antigen / immunology
  • CX3C Chemokine Receptor 1
  • Citrobacter rodentium / immunology
  • Citrobacter rodentium / pathogenicity*
  • Colon / immunology*
  • Colon / microbiology
  • Colon / pathology
  • Dendritic Cells / immunology
  • Dendritic Cells / microbiology
  • Dendritic Cells / pathology
  • Enterobacteriaceae Infections / immunology*
  • Enterobacteriaceae Infections / microbiology
  • Enterobacteriaceae Infections / mortality
  • Enterobacteriaceae Infections / pathology
  • Gene Expression Regulation
  • Homeostasis
  • Immunity, Innate
  • Immunity, Mucosal
  • Integrin alpha Chains / genetics
  • Integrin alpha Chains / immunology
  • Interferon-gamma / genetics
  • Interferon-gamma / immunology
  • Interleukin-12 / genetics
  • Interleukin-12 / immunology
  • Interleukin-23 / genetics
  • Interleukin-23 / immunology*
  • Interleukins / genetics
  • Interleukins / immunology
  • Intestinal Mucosa / immunology
  • Intestinal Mucosa / microbiology
  • Intestinal Mucosa / pathology
  • Macrophages / immunology*
  • Macrophages / microbiology
  • Macrophages / pathology
  • Mice
  • Mice, Transgenic
  • Monocytes / immunology*
  • Monocytes / microbiology
  • Monocytes / pathology
  • Receptors, Chemokine / genetics
  • Receptors, Chemokine / immunology
  • Signal Transduction
  • Survival Analysis
  • Th17 Cells / immunology
  • Th17 Cells / microbiology
  • Th17 Cells / pathology

Substances

  • Antigens, CD
  • CD11b Antigen
  • CX3C Chemokine Receptor 1
  • CX3CR1 protein, human
  • Integrin alpha Chains
  • Interleukin-23
  • Interleukins
  • Receptors, Chemokine
  • alpha E integrins
  • Interleukin-12
  • Interferon-gamma
  • interleukin-22