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Junctional epithelial Plakoglobin facilitates intestinal inflammation by p38MAPK-dependent activation of the inflammasome

ABSTRACT: Desmosomes play an underexplored role in intestinal homeostasis and are linked to the pathogenesis of inflammatory bowel diseases. We found a novel function of the desmosomal plaque protein Plakoglobin (JUP) in initiating the innate immune response to facilitate intestinal inflammation. Tissue samples from Crohn’s disease (CD) patients revealed a loss of JUP, which was mirrored in a mouse model of dextran sodium sulfate-induced (DSS) colitis. Inducible intestinal epithelial-specific knock-out of Jup (iVilCreERT2Jupfl/fl) in mice resulted in increased submucosal infiltration of macrophages and neutrophils, along with activation of the inflammasome. This was paralleled by p38MAPK phosphorylation, while loss of intestinal epithelial barrier function was absent. In DSS-colitis, epithelial Jup-deficiency impaired recovery and enhanced IL23/IL17-signaling. Intestinal organoids lacking Jup demonstrated NLRP1 inflammasome activation, indicated by increased IL1β and IL18 levels, which was attenuated by p38MAPK inhibition. In silico analysis and co-immunoprecipitation confirmed a direct interaction between JUP and p38MAPK, revealing a regulatory mechanism where JUP limits inflammasome signaling in intestinal epithelial cells. These effects were blunted by NLRP1/3 inhibitor ADS032. These findings identify JUP as a critical modulator of epithelial innate immunity in the gut. The loss of JUP in tissues from CD patients underscores its potential relevance in disease pathology.

ORGANISM(S): Mus musculus

PROVIDER: GSE282616 | GEO | 2025/08/14

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.

Project description:Purpose: PKM2-mediated metabolic switch to aerobic glycolysis plays a critical role in promoting cell survival and proliferation. However, little is known about the function of intestinal epithelial PKM2 in intestinal homeostasis. Here we investigated whether and how intestinal epithelial PKM2 modulates the morphology and function of the adult intestine in experimental murine colitis. Methods: Colonoscopic biopsies from the Crohn’s disease (CD) and ulcerative colitis (UC) patients (10 each) were analyzed for PKM2 expression. We also generated intestinal epithelial-specific Pkm2 knockout mice and employed them to examine PKM2 function. Mouse intestinal inflammation was induced with dextran sulfate sodium (DSS) in drinking water. Disease phenotypes were investigated by mouse survival, body weight, colon length and analysis of immune cell infiltration in colon, intestinal epithelial cell gene profiling and signal pathway. Results: Intestinal epithelial PKM2 level in UC and CD patients was significantly decreased compared to that from non-inflamed intestinal epithelium. Similar reduction of intestinal epithelial PKM2 was observed in mice with experimental colitis. Supporting the notion that PKM2 serves as a safeguard against colitis, intestinal epithelial-specific Pkm2-deficient (Pkm2-/-) mice displayed a severer intestinal inflammation, companying with shortened colon, disruption of epithelial tight junction, higher permeability, elevation of inflammatory cytokines and immune cell infiltration, compared with wild-type mice. Gene profiling and western blot analysis indicated that cell survival signaling, particularly the Akt/β-catenin pathways, were downregulated in Pkm2-/- mice. Functional assay using mouse primary colonic epithelial cells confirmed that Pkm2 reduction decreased proliferation and migration of epithelial cells, while enhanced expression of Pkm2 was associated with increased transcriptional activity of β-catenin. Moreover, increasing mouse intestinal epithelial Pkm2 expression via delivery of Pkm2-expressing plasmid attenuated DSS-induced experimental colitis. Conclusions: Intestinal epithelial PKM2, through activating Wnt/β-catenin signaling, induces a strong proliferative and migratory response that increases cell survival and wound healing under colitic condition.

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Junctional epithelial Plakoglobin facilitates intestinal inflammation by p38MAPK-dependent activation of the inflammasome

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