title: IL-23-mediated mononuclear phagocyte crosstalk protects mice from Citrobacter rodentium-induced colon immunopathology.
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.
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Tegest
authors.initials: T
authors.lastname: Aychek
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Alexander
authors.initials: A
authors.lastname: Mildner
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Simon
authors.initials: S
authors.lastname: Yona
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Ki-Wook
authors.initials: KW
authors.lastname: Kim
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Nardy
authors.initials: N
authors.lastname: Lampl
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Shlomit
authors.initials: S
authors.lastname: Reich-Zeliger
authors.affiliation: Bioceros, Yalelaan 46, 3584 CM Utrecht, The Netherlands.
authors.forename: Louis
authors.initials: L
authors.lastname: Boon
authors.affiliation: Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University, 55131 Mainz, Germany.
authors.forename: Nir
authors.initials: N
authors.lastname: Yogev
authors.affiliation: Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University, 55131 Mainz, Germany.
authors.forename: Ari
authors.identifier: 0000000343048234
authors.initials: A
authors.lastname: Waisman
authors.affiliation: Merck Research Laboratories, 901 South California Avenue, Palo Alto, California 94304-1104, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Cua
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Steffen
authors.initials: S
authors.lastname: Jung
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D039481:CD11b Antigen / Q000235:genetics / Q000276:immunology; D000073883:CX3C Chemokine Receptor 1; D044082:Citrobacter rodentium / Q000276:immunology / Q000472:pathogenicity*; D003106:Colon / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D003713:Dendritic Cells / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D004756:Enterobacteriaceae Infections / Q000276:immunology* / Q000382:microbiology / Q000401:mortality / Q000473:pathology; D005786:Gene Expression Regulation; D006706:Homeostasis; D007113:Immunity, Innate; D018928:Immunity, Mucosal; D039001:Integrin alpha Chains / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology; D053759:Interleukin-23 / Q000235:genetics / Q000276:immunology*; D007378:Interleukins / Q000235:genetics / Q000276:immunology; D007413:Intestinal Mucosa / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009000:Monocytes / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D019707:Receptors, Chemokine / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D016019:Survival Analysis; D058504:Th17 Cells / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D000097043:Interleukin-22
chemical_list: D015703:Antigens, CD; D039481:CD11b Antigen; D000073883:CX3C Chemokine Receptor 1; D039001:Integrin alpha Chains; D007371:Interferon-gamma; D018664:Interleukin-12; D053759:Interleukin-23; D007378:Interleukins; D019707:Receptors, Chemokine; D000097043:Interleukin-22; C095235:CX3CR1 protein, human; C091367:alpha E integrins