Intestinal permeability regulation by tight junction: implication on inflammatory bowel diseases

Abstract

Epithelial tight junctions (TJs) are the key structures regulating paracellular trafficking of macromolecules. The TJ is multi-protein complex that forms a selective permeable seal between adjacent epithelial cells and demarcates the boundary between apical and basolateral membrane domains. Disruption of the intestinal TJ barrier, followed by permeation of luminal noxious molecules, induces a perturbation of the mucosal immune system and inflammation, which can act as a trigger for the development of intestinal and systemic diseases. Inflammatory bowel disease (IBD) patients demonstrate increased intestinal paracellular permeability. Although it remains unclear whether barrier dysfunction precedes disease or results from active inflammation, increased intestinal TJ disruption is observed in IBD patients suggest that dysregulation of TJ barrier integrity may predispose or enhance IBD progression. Therefore, therapeutic target to restore the TJ barrier integrity may provide effective therapeutic and preventive approaches against IBD. This review discusses the molecular structure and regulation of intestinal TJs and the involvement of intestinal TJs in IBD pathogenesis.

Keywords: Inflammatory bowel diseases; Intestinal barrier function; Intestinal permeability; Paracellular permeability; Tight junctions.

Fig. 1

Molecular structure of the intracellular junction of intestinal epithelial cells. The tight junctions (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 transmembrane proteins (claudins, occludin, and junctional adhesion molecules [JAMs]) create a permselective barrier in the paracellular pathways. The intracellular domains of the transmembrane proteins interact with the intracellular scaffold proteins such as zonula occludens (ZO) proteins, which in turn anchor the transmembrane proteins to the actin cytoskeleton.

Fig. 2

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 (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. JAM-A, junctional adhesion molecule-A.