Targeting desmosomal adhesion and signalling for intestinal barrier stabilization in inflammatory bowel diseases—Lessons from experimental models and patients

Abstract

Inflammatory bowel diseases (IBD) such as Crohn’s disease (CD) and Ulcerative colitis (UC) have a complex and multifactorial pathogenesis which is incompletely understood. A typical feature closely associated with clinical symptoms is impaired intestinal epithelial barrier function. Mounting evidence suggests that desmosomes, which together with tight junctions (TJ) and adherens junctions (AJ) form the intestinal epithelial barrier, play a distinct role in IBD pathogenesis. This is based on the finding that desmoglein (Dsg) 2, a cadherin‐type adhesion molecule of desmosomes, is required for maintenance of intestinal barrier properties both in vitro and in vivo, presumably via Dsg2‐mediated regulation of TJ. Mice deficient for intestinal Dsg2 show increased basal permeability and are highly susceptible to experimental colitis. In several cohorts of IBD patients, intestinal protein levels of Dsg2 are reduced and desmosome ultrastructure is altered suggesting that Dsg2 is involved in IBD pathogenesis. In addition to its adhesive function, Dsg2 contributes to enterocyte cohesion and intestinal barrier function. Dsg2 is also involved in enterocyte proliferation, barrier differentiation and induction of apoptosis, in part by regulation of p38MAPK and EGFR signalling. In IBD, the function of Dsg2 appears to be compromised via p38MAPK activation, which is a critical pathway for regulation of desmosomes and is associated with keratin phosphorylation in IBD patients. In this review, the current findings on the role of Dsg2 as a novel promising target to prevent loss of intestinal barrier function in IBD patients are discussed.

Ulcerative Colitis-Derived Colonoid Culture: A Multi-Mineral-Approach to Improve Barrier Protein Expression

“…Most studies have focused on tight junctional complexes as the primary regulator of permeability, and high-fat or high-sugar intake has been shown to affect these structures (Moreira et al, 2012;Thaiss et al, 2018). Similarly, it has been demonstrated that intestinal desmoglein-2, an adhesion molecule of desmosomes, is required for the maintenance of intestinal barrier and its deficiency cause increased barrier permeability (Schlegel et al, 2020). Our own work has demonstrated the importance of calcium as a regulator of the colonic barrier.…”

Intestinal Epithelial Barrier Maturation by Enteric Glial Cells Is GDNF-Dependent

“…The intestinal epithelial barrier (IEB) plays an essential role in health and disease. This barrier is maintained by polarized and highly specialized cells, including enterocytes, goblet cells, Paneth cells, enteroendocrine cells and M-cells which line the whole gut lumen [ 1 , 2 , 3 ]. The intercellular space between these cells is sealed by different junctional proteins such as tight junctions, adherens junctions and desmosomes, which together form the apical junctional complex [ 3 ].…”

“…This barrier is maintained by polarized and highly specialized cells, including enterocytes, goblet cells, Paneth cells, enteroendocrine cells and M-cells which line the whole gut lumen [ 1 , 2 , 3 ]. The intercellular space between these cells is sealed by different junctional proteins such as tight junctions, adherens junctions and desmosomes, which together form the apical junctional complex [ 3 ]. Dysregulation of IEB function caused by loss of junctional proteins in the apical junctional complex represents a hallmark in the pathogenesis and perpetuation of inflammatory bowel diseases (IBD) [ 3 , 4 ].…”

“…The intercellular space between these cells is sealed by different junctional proteins such as tight junctions, adherens junctions and desmosomes, which together form the apical junctional complex [ 3 ]. Dysregulation of IEB function caused by loss of junctional proteins in the apical junctional complex represents a hallmark in the pathogenesis and perpetuation of inflammatory bowel diseases (IBD) [ 3 , 4 ].…”

Simulating the Post-gastric Bypass Intestinal Microenvironment Uncovers a Barrier-Stabilizing Role for FXR

“…The intestinal epithelial barrier (IEB) comprises a single continuous layer of cells lining the gastrointestinal tract and serves as the main line of defense against ingested toxins and potentially pathogenic microbes residing in the gastrointestinal wall and lumen ( Vancamelbeke and Vermeire, 2017 ). Tight junctions, adherens junctions, and desmosomes are multi-protein complexes located to the cell membrane of enterocytes that together form a homophilic, tripartite seal from the apical to the basolateral sides, respectively ( Garcia et al., 2018 ; Heinemann and Schuetz, 2019 ; Schlegel et al., 2020 ). Since the original findings in mice ( Cani et al., 2007 , 2008 ), evidence has mounted that obesity is associated with IEB breakdown primarily due to unfavorable shifts in the intestinal microbiota caused by frequent overconsumption of a high-fat diet ( Chakaroun et al., 2020 ).…”