IL-22-Activated MUC13 Impacts on Colonic Barrier Function through JAK1/STAT3, SNAI1/ZEB1 and ROCK2/MAPK Signaling

Abstract

Overexpression of the transmembrane mucin MUC13, as seen in inflammatory bowel diseases (IBD), could potentially impact barrier function. This study aimed to explore how inflammation-induced MUC13 disrupts epithelial barrier integrity by affecting junctional protein expression in IBD, thereby also considering the involvement of MUC1. RNA sequencing and permeability assays were performed using LS513 cells transfected with MUC1 and MUC13 siRNA and subsequently stimulated with IL-22. In vivo intestinal permeability and MUC13-related signaling pathways affecting barrier function were investigated in acute and chronic DSS-induced colitis wildtype and Muc13−/−mice. Finally, the expression of MUC13, its regulators and other barrier mediators were studied in IBD and control patients. Mucin knockdown in intestinal epithelial cells affected gene expression of several barrier mediators in the presence/absence of inflammation. IL-22-induced MUC13 expression impacted barrier function by modulating the JAK1/STAT3, SNAI1/ZEB1 and ROCK2/MAPK signaling pathways, with a cooperating role for MUC1. In response to DSS, MUC13 was protective during the acute phase whereas it caused more harm upon chronic colitis. The pathways accounting for the MUC13-mediated barrier dysfunction were also altered upon inflammation in IBD patients. These novel findings indicate an active role for aberrant MUC13 signaling inducing intestinal barrier dysfunction upon inflammation with MUC1 as collaborating partner.

MUC13 negatively regulates tight junction proteins and intestinal epithelial barrier integrity via protein kinase C

“…Our observations about the link between MUC13 and TJs shed new light on previous reports showing alterations of TJ proteins in individuals with IBD. The main TJ proteins occludin and tricellulin, together with sealing claudins (such as claudins-3, -4, -5, -7 and -8) are downregulated in colonic and rectal tissue of individuals with IBD, whereas claudin-1 and the pore-forming claudin-2 are upregulated, leading to reduced barrier function ( Heller et al, 2005 ; Prasad et al, 2005 ; Zeissig et al, 2007 ; Oshima et al, 2008 ; Weber et al, 2008 ; Breugelmans et al, 2023 ). The negative regulation of intestinal barrier MUC13 that we observed in our model might in part explain the loss of intestinal integrity in individuals with IBD.…”