title: Epithelial IL-18 Equilibrium Controls Barrier Function in Colitis.
abstract: The intestinal mucosal barrier controlling the resident microbiome is dependent on a protective mucus layer generated by goblet cells, impairment of which is a hallmark of the inflammatory bowel disease, ulcerative colitis. Here, we show that IL-18 is critical in driving the pathologic breakdown of barrier integrity in a model of colitis. Deletion of Il18 or its receptor Il18r1 in intestinal epithelial cells (Δ/EC) conferred protection from colitis and mucosal damage in mice. In contrast, deletion of the IL-18 negative regulator Il18bp resulted in severe colitis associated with loss of mature goblet cells. Colitis and goblet cell loss were rescued in Il18bp(-/-);Il18r(Δ/EC) mice, demonstrating that colitis severity is controlled at the level of IL-18 signaling in intestinal epithelial cells. IL-18 inhibited goblet cell maturation by regulating the transcriptional program instructing goblet cell development. These results inform on the mechanism of goblet cell dysfunction that underlies the pathology of ulcerative colitis.
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Roni
authors.initials: R
authors.lastname: Nowarski
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Ruaidhrí
authors.initials: R
authors.lastname: Jackson
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Nicola
authors.initials: N
authors.lastname: Gagliani
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Marcel R
authors.initials: MR
authors.lastname: de Zoete
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Noah W
authors.initials: NW
authors.lastname: Palm
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Will
authors.initials: W
authors.lastname: Bailis
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Jun Siong
authors.initials: JS
authors.lastname: Low
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Christian C D
authors.initials: CC
authors.lastname: Harman
authors.affiliation: Center for Cellular and Molecular Imaging, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Morven
authors.initials: M
authors.lastname: Graham
authors.affiliation: Immunology Department, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Eran
authors.initials: E
authors.lastname: Elinav
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Howard Hughes Medical Institute, Yale University, New Haven, CT 06520, USA. Electronic address: richard.flavell@yale.edu.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
mesh_terms: D000818:Animals; D003093:Colitis, Ulcerative / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D016264:Dextran Sulfate; D042783:Endothelial Cells / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology; D005260:Female; D020397:Goblet Cells / Q000378:metabolism / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D020382:Interleukin-18 / Q000276:immunology*; D053727:Interleukin-18 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism; D007413:Intestinal Mucosa / Q000503:physiopathology; D008297:Male; D051379:Mice; D015398:Signal Transduction
chemical_list: C508573:Il18r1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18; D053727:Interleukin-18 Receptor alpha Subunit; C118370:interleukin-18 binding protein; D016264:Dextran Sulfate