Regulation of intestinal epithelial permeability by tight junctions

Abstract

The gastrointestinal epithelium forms the boundary between the body and external environment. It effectively provides a selective permeable barrier that limits the permeation of luminal noxious molecules, such as pathogens, toxins, and antigens, while allowing the appropriate absorption of nutrients and water. This selective permeable barrier is achieved by intercellular tight junction (TJ) structures, which regulate paracellular permeability. Disruption of the intestinal TJ barrier, followed by permeation of luminal noxious molecules, induces a perturbation of the mucosal immune system and inflammation, and can act as a trigger for the development of intestinal and systemic diseases. In this context, much effort has been taken to understand the roles of extracellular factors, including cytokines, pathogens, and food factors, for the regulation of the intestinal TJ barrier. Here, I discuss the regulation of the intestinal TJ barrier together with its implications for the pathogenesis of diseases.

Fig. 1

Barrier function of intestinal tight junctions (TJs). The intestinal epithelium provides a physical barrier to luminal bacteria, toxins, and antigens. The barrier is organized by different barrier components, including the TJs. The TJs regulate the paracellular passages of ions, solutes, and water between adjacent cells. Luminal noxious macromolecules cannot penetrate the epithelium because of the TJ barrier; however, TJ barrier impairment allows the passage of noxious molecules, which can induce the excessive activation of mucosal immune cells and inflammation. Therefore, intestinal barrier defects are associated with the initiation and development of various intestinal and systemic diseases

Fig. 2

Molecular structure of the intercelluar junction of intestinal epithelial cells. The intercellular junctions of intestinal epithelial cells are sealed by different protein complexes, including TJs, adherens junctions (AJs), and desmosomes. The TJs, multiple protein complexes, locate at the apical ends of the lateral membranes of intestinal epithelial cells. The TJ complex consists of transmembrane and intracellular scaffold proteins. The extracellular loops of the transmembrane proteins (occludin, claudins, JAMs, and tricellulin) create a permselective barrier in the paracellular pathways by hemophilic and heterophilic interactions with adjacent cells. The intracellular domains of the transmembrane proteins interact with the intracellular scaffold proteins such as zonula occludens (ZO) proteins and cingulin, which in turn anchor the transmembrane proteins to the actin cytoskeleton. Myosin light chain kinase (MLCK) is associated with the perijuctional actomyosin rings and regulates paracellular permeability through myosin contractility. The AJs along with desmosomes provide strong adhesive bonds between the epithelial cells and also intercellular communication, but do not determine paracellular permeability

Fig. 3

Interaction of proteins with the integral scaffold tight junction (TJ) proteins, zonula occludens (ZO)-1, -2, and -3. ZO proteins carry 3 post-synaptic density 95/Drosophila disc large/zona-occludens 1 (PDZ) domains, a Src homology-3 (SH3) domain, and a region of homology to guanylate kinase (GUK) from the side of the N-terminus. Several TJ proteins and cytoskeletal actin interact with the ZO proteins