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

Tegest Aychek, Alexander Mildner, Simon Yona, Ki-Wook Kim, Nardy Lampl, Shlomit Reich-Zeliger, Louis Boon, Nir Yogev, Ari Waisman, Daniel J. Cua and Steffen Jung ()
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Tegest Aychek: Weizmann Institute of Science
Alexander Mildner: Weizmann Institute of Science
Simon Yona: Weizmann Institute of Science
Ki-Wook Kim: Weizmann Institute of Science
Nardy Lampl: Weizmann Institute of Science
Shlomit Reich-Zeliger: Weizmann Institute of Science
Louis Boon: Bioceros
Nir Yogev: Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University
Ari Waisman: Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University
Daniel J. Cua: Merck Research Laboratories
Steffen Jung: Weizmann Institute of Science

Nature Communications, 2015, vol. 6, issue 1, 1-10

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7525

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