E-cadherin Is Important for the Maintenance of Intestinal Epithelial Homeostasis Under Basal and Inflammatory Conditions

Excerpt

The intestinal epithelial layer forms an important barrier that protects underlying tissues from bacteria within the gut lumen. This single monolayer is comprised of epithelial cells that are connected by intercellular junctions. The most apical junctions are tight junctions (TJ) followed by adherens junctions (AJ) and desmosomes. AJ mediate cell–cell adhesion mainly via E-cadherin. Cell junctions are dynamic structures that continuously need to respond to stimuli that may stabilize or destabilize inter-epithelial cell contacts. Inflammatory cytokines activate mediators of signaling pathways such as small GTPases that destabilize junctions by internalization or proteolysis of junction molecules, including E-cadherin [1‐3]. Such processing disconnects junctions from the actin cytoskeleton, consequently destabilizing cell contacts that facilitate invasion of pathogens to further trigger inflammation. If not controlled or resolved properly, such destabilization may lead to the development of chronic inflammatory conditions such as inflammatory bowel diseases (IBD), including ulcerative colitis and Crohn’s disease. IBD are characterized by increased intestinal epithelial permeability, painful cramping, bloody diarrhea, and weight loss [4]. Since the pathogenesis of IBD and curative treatments remain elusive, the study of the pathologic derangements of molecular mechanisms associated with IBD is important in the development of novel treatment strategies. In this respect transmembranal junctional adhesion molecules are important because they directly mediate cell–cell adhesion and thus stabilize the entire epithelial monolayer. For example, the physiological significance of E-cadherin has been investigated intensively using in vivo and in vitro models simulating the clinical and pathological manifestations of IBD [5]. The use of E-cadherin knockout (KO) and knockin mouse models in the study of tissue-specific effects of E-cadherin loss or replacement has recently been reviewed [6]. Of note, total E-cadherin KO in mice is embryonically lethal [7]. Intestinal-specific deletion of the floxed CDH1 gene using Villin-Cre mice was associated with death within 24 h after birth [8]. Targeted E-cadherin deletion was induced in adult mice using a tamoxifen-induced deletion that was associated with bloody diarrhea with death attributed to epithelial shedding [9]. These data highlight the importance of E-cadherin for intestinal epithelial homeostasis even under basal conditions. In vitro, inflammatory conditions, simulated by IFN-γ treatment of T84 cells, reduced surface expression of E-cadherin, enhanced AJ disassembly, and overall destabilized the epithelial monolayer [10]. Yet, it remained elusive how the induced loss of E-cadherin would affect the development of colitis in vivo (Fig. 1).

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