Intestinal barrier function: molecular regulation and disease pathogenesis

Abstract

The intestinal epithelium is a single-cell layer that constitutes the largest and most important barrier against the external environment. It acts as a selectively permeable barrier, permitting the absorption of nutrients, electrolytes, and water while maintaining an effective defense against intraluminal toxins, antigens, and enteric flora. The epithelium maintains its selective barrier function through the formation of complex protein-protein networks that mechanically link adjacent cells and seal the intercellular space. The protein networks connecting epithelial cells form 3 adhesive complexes: desmosomes, adherens junctions, and tight junctions. These complexes consist of transmembrane proteins that interact extracellularly with adjacent cells and intracellularly with adaptor proteins that link to the cytoskeleton. Over the past decade, there has been increasing recognition of an association between disrupted intestinal barrier function and the development of autoimmune and inflammatory diseases. In this review we summarize the evolving understanding of the molecular composition and regulation of intestinal barrier function. We discuss the interactions between innate and adaptive immunity and intestinal epithelial barrier function, as well as the effect of exogenous factors on intestinal barrier function. Finally, we summarize clinical and experimental evidence demonstrating intestinal epithelial barrier dysfunction as a major factor contributing to the predisposition to inflammatory diseases, including food allergy, inflammatory bowel diseases, and celiac disease.

Figure 1. Pathways of epithelial permeability

Transcellular permeability is associated with solute or water movement through intestinal epithelial cells. Paracellular permeability is associated with movement in the intercellular space between epithelial cells and is regulated by tight junctions localized at the junction of the apical-lateral membranes.

Figure 2. Overview of intestinal epithelial junctional complexes

The intestinal epithelium consists of a single layer of polarized epithelial cells. Adjacent cells are connected by 3 main junctional complexes: desmosomes, adherens junctions and tight junctions. Desmosomes are localized dense plaques that are connected to keratin filaments. Adherens and tight junctions both consist of transcellular proteins connected intracellularly via adaptor proteins to the actin cytoskeleton. The collection of proteins in the junctional complexes form “cytoplasmic plaques”.

Figure 3. Tight Junctions

TJs are localized to the apical-lateral membrane junction. They consist of integral transmembrane proteins (occludin, claudins and junctional adhesion molecules (JAMs)) that interact in the paracellular space with proteins on adjacent cells. Interactions can be homophilic (eg claudin-1/claudin-1) or heterophilic (claudin-1/claudin-3). The intracellular domains of transmembrane proteins interact with PDZ-domain-containing adaptor proteins that mechanically link the TJ complex to the actin cytoskeleton. TJ proteins are regulated by phosphorylation by kinases, phosphatases and other signaling molecules.

Figure 4. Immune regulation of intestinal barrier function

T-cell-derived IFNγ and TNFα inhibit MLCK-mediated phosphorylation of myosin light chain leading to TJ junction disruption and intestinal barrier dysfunction. IFNγ can also promote the redistribution of TJ proteins, JAM-A, occludin, claudin-1 and claudin-4 from the apical TJ border by a micropinocytosis process. TNFα and IFNγ may alternatively disrupt TJ stability and increase intestinal permeability via dysregulation of occludin expression. IL-4 and IL-13-induced increase in intestinal permeability is mediated via induction of epithelial apoptosis and expression of the pore-forming tight junction protein claudin-2. IL-4 and not IL-13 regulates ion conductance via downregulation of epithelial CFTR Cl⁻ channel expression. Intraepithelial (iIEL)γδ⁺ lymphocytes (TCR-Vγ7⁺) iIEL cells are important in serine phosphorylation of occludin and TJ stabilization. Mast cell mediators including cytokine TNFα, mast cell protease 1 (mcpt-1) and lipid mediators including histamine, PAF and prostaglandins promote increased Cl⁻ conductance and increase intestinal permeability. Mcpt1 degrades the TJ protein occludin altering barrier function Eosinophil derived MBP down regulates tight junction protein occludin-1 expression in colonic epithelial cells.