Epithelial IL-18 Equilibrium Controls Barrier Function in Colitis

Roni Nowarski; Ruaidhrí Jackson; Nicola Gagliani; Marcel R de Zoete; Noah W Palm; Will Bailis; Jun Siong Low; Christian C D Harman; Morven Graham; Eran Elinav; Richard A Flavell

doi:10.1016/j.cell.2015.10.072

Epithelial IL-18 Equilibrium Controls Barrier Function in Colitis

Roni Nowarski, Ruaidhrí Jackson, Nicola Gagliani, Marcel R de Zoete, Noah W Palm, Will Bailis, Jun Siong Low, Christian C D Harman, Morven Graham, Eran Elinav, Richard A Flavell

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Pages (from-to)	1444-56
Number of pages	13
Journal	Cell
Volume	163
Issue number	6
DOIs	https://doi.org/10.1016/j.cell.2015.10.072
Publication status	Published - 3 Dec 2015
Externally published	Yes

Keywords

Animals
Colitis, Ulcerative/chemically induced
Dextran Sulfate
Endothelial Cells/metabolism
Epithelial Cells/cytology
Female
Goblet Cells/metabolism
Intercellular Signaling Peptides and Proteins/genetics
Interleukin-18/immunology
Interleukin-18 Receptor alpha Subunit/genetics
Intestinal Mucosa/physiopathology
Male
Mice
Signal Transduction

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10.1016/j.cell.2015.10.072

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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. ",

keywords = "Animals, Colitis, Ulcerative/chemically induced, Dextran Sulfate, Endothelial Cells/metabolism, Epithelial Cells/cytology, Female, Goblet Cells/metabolism, Intercellular Signaling Peptides and Proteins/genetics, Interleukin-18/immunology, Interleukin-18 Receptor alpha Subunit/genetics, Intestinal Mucosa/physiopathology, Male, Mice, Signal Transduction",

author = "Roni Nowarski and Ruaidhr{\'i} Jackson and Nicola Gagliani and \{de Zoete\}, \{Marcel R\} and Palm, \{Noah W\} and Will Bailis and Low, \{Jun Siong\} and Harman, \{Christian C D\} and Morven Graham and Eran Elinav and Flavell, \{Richard A\}",

year = "2015",

month = dec,

day = "3",

doi = "10.1016/j.cell.2015.10.072",

language = "English",

volume = "163",

pages = "1444--56",

journal = "Cell",

issn = "0092-8674",

publisher = "Elsevier",

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T1 - Epithelial IL-18 Equilibrium Controls Barrier Function in Colitis

AU - Nowarski, Roni

AU - Jackson, Ruaidhrí

AU - Gagliani, Nicola

AU - de Zoete, Marcel R

AU - Palm, Noah W

AU - Bailis, Will

AU - Low, Jun Siong

AU - Harman, Christian C D

AU - Graham, Morven

AU - Elinav, Eran

AU - Flavell, Richard A

PY - 2015/12/3

Y1 - 2015/12/3

N2 - 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.

AB - 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.

KW - Animals

KW - Colitis, Ulcerative/chemically induced

KW - Dextran Sulfate

KW - Endothelial Cells/metabolism

KW - Epithelial Cells/cytology

KW - Female

KW - Goblet Cells/metabolism

KW - Intercellular Signaling Peptides and Proteins/genetics

KW - Interleukin-18/immunology

KW - Interleukin-18 Receptor alpha Subunit/genetics

KW - Intestinal Mucosa/physiopathology

KW - Male

KW - Mice

KW - Signal Transduction

U2 - 10.1016/j.cell.2015.10.072

DO - 10.1016/j.cell.2015.10.072

M3 - Article

C2 - 26638073

SN - 0092-8674

VL - 163

SP - 1444

EP - 1456

JO - Cell

JF - Cell

IS - 6

ER -

Epithelial IL-18 Equilibrium Controls Barrier Function in Colitis

Abstract

Keywords

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