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Mouse models using an intestinal epithelial-specific and inducible VilCreERT2-mediated conditional knockout of Jup under basal conditions and in acute dextran-sodium sulfate (DSS)-induced colitis

ABSTRACT: Investigation of microbial community composition in mouse models using an intestinal epithial-specific and inducible VilCreERT2-mediated conditional knockout of Jup under basal conditions and in acute dextran-sodium sulfate (DSS)-induced colitis We investigated the gut microbiome composition in a dextran sulfate sodium (DSS) colitis model using Jupfl/fl and iVilCreERT2Jupfl/fl mice. Fecal samples were collected after DSS treatment, and 16S rRNA sequencing was employed to analyze microbial communities. Our findings revealed no significant differences in microbial profiles between Jupfl/fl and iVilCreERT2Jupfl/fl under DSS treatment.

ORGANISM(S): Mus musculus

PROVIDER: GSE280535 | GEO | 2025/09/03

REPOSITORIES: GEO

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Project description:Background and Aims: Desmosomes play an underexplored role in intestinal epithelial homeostasis and have been linked to the pathogenesis of inflammatory bowel diseases. Here, we assessed a novel function of the desmosomal plaque protein plakoglobin (JUP) in initiating the innate immune response that facilitates intestinal inflammation. Methods: Surgical tissue samples of patients with Crohn’s Disease (CD) were collected and characterized for junctional protein changes. Mouse models using an intestinal epithelial-specific and inducible VilCreERT2-mediated conditional knockout of Jup under basal conditions and in acute dextran-sodium sulfate (DSS)-induced colitis were characterized using functional analyses, single cell and bulk sequencing. Intestinal organoids served to determine molecular mechanisms. Results: In patients with CD and in murine DSS colitis, loss of JUP was evident. Intestinal epithelial-specific knockout of Jup in mice resulted in augmented submucosal infiltration of macrophages and neutrophils and in an overall activation of the inflammasome. However, loss of intestinal barrier function, bacterial translocation or altered microbial composition were absent under basal conditions. In DSS-induced colitis, epithelial Jup-deficiency led to increased disease activity and strong activation of interleukin IL23/17-signalling compared to littermate controls with neutrophils representing the major source of IL23 under these conditions. Mechanistically, intestinal epithelial organoids lacking Jup demonstrated robust NLRP1 inflammasome activation due to p38MAPK hyperphosphorylation. This activation was evidenced by increased expression of NLRP1, IL1β, and IL18 in Jup-deficient intestinal epithelial cells, which was mitigated by p38MAPK inhibition. Conclusion: These findings point to a novel role for JUP in initiating intestinal inflammation. The loss of JUP in tissues from CD patients underscores its potential relevance in disease pathology.

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Mouse models using an intestinal epithelial-specific and inducible VilCreERT2-mediated conditional knockout of Jup under basal conditions and in acute dextran-sodium sulfate (DSS)-induced colitis

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