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

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.