Disruption of the epithelial barrier during intestinal inflammation: Quest for new molecules and mechanisms

Abstract

The intestinal epithelium forms a key protective barrier that separates internal organs from the harmful environment of the gut lumen. Increased permeability of the gut barrier is a common manifestation of different inflammatory disorders contributing to the severity of disease. Barrier permeability is controlled by epithelial adherens junctions and tight junctions. Junctional assembly and integrity depend on fundamental homeostatic processes such as cell differentiation, rearrangements of the cytoskeleton, and vesicle trafficking. Alterations of intestinal epithelial homeostasis during mucosal inflammation may impair structure and remodeling of apical junctions, resulting in increased permeability of the gut barrier. In this review, we summarize recent advances in our understanding of how altered epithelial homeostasis affects the structure and function of adherens junctions and tight junctions in the inflamed gut. Specifically, we focus on the transcription reprogramming of the cell, alterations in the actin cytoskeleton, and junctional endocytosis and exocytosis. We pay special attention to knockout mouse model studies and discuss the relevance of these mechanisms to human gastrointestinal disorders.

Keywords: Actin cytoskeleton; Adherens junctions; Endocytosis; Exocytosis; Non-muscle myosin II; Tight junctions.

Figure 1. Different mechanisms that mediate disassembly of adherens junctions and tight junctions in the inflamed intestinal mucosa

This schematic diagram summarizes the major mechanisms that contribute to intestinal AJ and TJ disassembly during mucosal inflammation. Different cellular responses such as altered expression of junctional proteins, cytoskeletal abnormalities, and altered vesicle trafficking are marked by different colors.

Figure 2. Vesicle trafficking mechanisms that regulate the integrity and disruption of the intestinal epithelial barrier

The diagram depicts a balanced vesicle trafficking cycle that regulates proper assembly of epithelial junction in normal intestinal mucosa. Altering this cycle by either increasing endocytosis or inhibiting exocytosis of junctional proteins results in AJ and TJ disassembly.

Figure 3. Regulation of epithelial apical junctions by the actin cytoskeleton

The diagram shows association of epithelial AJs and TJs with the cortical actin cytoskeleton. Major actin-binding proteins, cytoskeletal motors, and signaling molecules that are known to regulate intestinal epithelial junctions are presented.