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: 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
• Journal: Cell (Cell) Vol. 163 Issue 6 Pg. 1444-56 (Dec 03 2015) ISSN: 1097-4172 [Electronic] United States
• PMID: 26638073 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Il18r1 protein, mouse
• Intercellular Signaling Peptides and Proteins
• Interleukin-18
• Interleukin-18 Receptor alpha Subunit
• interleukin-18 binding protein
• Dextran Sulfate

Topics

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