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 journalArticleAcademicpeer-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 languageEnglish
    Pages (from-to)1444-1456
    Number of pages13
    JournalCell
    Volume163
    Issue number6
    DOIs
    Publication statusPublished - 3 Dec 2015

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