Epithelial IL-18 Equilibrium Controls Barrier Function in Colitis

Abstract

SUMMARY 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−/−;Il18rΔ/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 which underlies the pathology of Ulcerative Colitis.

Autophagy deficiency in myeloid cells increases susceptibility to obesity-induced diabetes and experimental colitis

“…39,41 Aggravated inflammation in DSS-treated Atg7 cKO mice compared to Atg7 cWT mice might be related to the recently reported colitogenic role of IL18 that can be produced through the inflammasome in DSS-induced colitis. 65 We also observed skewing toward Th1 in colonic lamina propria of DSS-treated Atg7 cKO mice compared to Atg7 cWT mice. Th17 skewing was not observed in colonic lamina propria of DSS-treated Atg7 cKO mice despite the increased expression of pro-Il1b and Il6 that are important components in Th17 differentiation, 44,66 which could be due to the absence of Tgfb induction in colonic lamina propria of DSS-treated Atg7 cKO mice.…”

Nlrp3-dependent IL-1β inhibits CD103+ dendritic cell differentiation in the gut

“…(18,23,42). Our data are concordant with a recent report on miR-223-mediated regulation of Nlrp3 expression and intestinal inflammation, describing Nlrp3-dependent elevation of IL-1, but not of IL-18, levels (20).…”

“…Although elevated IL-18 levels are observed in IBD patients and in animal models, both protective and deleterious effects of IL-18 signaling have been reported (17,18). One explanation is that intestinal IL-1β is mostly produced by myeloid cells, whereas IL-18 is constitutively expressed in epithelial cells and seems to regulate mucosal homeostasis (18).…”

Inflammasomes make the case for littermate-controlled experimental design in studying host-microbiota interactions

“…Indeed, littermate-controlled DSS experiments using epithelial IL-18-deficient mice (IL-18 IEC-KO ) had previously shown a detrimental role for IL-18 production during DSS colitis development. 29 As Nlrp6 deficiency in our gut microbiota normalized DSS experiments did not exhibit protective effects, other caspase-1 inflammasomes presumably can produce sufficient amounts of mature IL-18 in the absence of Nlrp6. As it is plausible that the activation of these Nlrp6-independent inflammasomes depends on the nature and the activity of the intestinal microbiota, it will be interesting to identify the ligands and the inflammasomes responsible for this IL-18 production in future studies.…”