Alpha-tocopherylquinone differentially modulates claudins to enhance intestinal epithelial tight junction barrier via AhR and Nrf2 pathways.

Defects in intestinal epithelial tight junctions (TJs) allow paracellular permeation of noxious luminal antigens and are important pathogenic factors in inflammatory bowel disease (IBD). We show that alpha-tocopherylquinone (TQ), a quinone-structured oxidation product of vitamin E, consistently enhances the intestinal TJ barrier by increasing barrier-forming claudin-3 (CLDN3) and reducing channel-forming CLDN2 in Caco-2 cell monolayers (in vitro), mouse models (in vivo), and surgically resected human colons (ex vivo). TQ reduces colonic permeability and ameliorates colitis symptoms in multiple colitis models.

Long-Term Use of Proton Pump Inhibitors Disrupts Intestinal Tight Junction Barrier and Exaggerates Experimental Colitis.

Background: Proton pump inhibitors [PPIs] are widely used to treat a number of gastro-oesophageal disorders. PPI-induced elevation in intragastric pH may alter gastrointestinal physiology. The tight junctions [TJs] residing at the apical intercellular contacts act as a paracellular barrier.

AP2M1 mediates autophagy-induced CLDN2 (claudin 2) degradation through endocytosis and interaction with LC3 and reduces intestinal epithelial tight junction permeability.

The intestinal epithelial tight junctions (TJs) provide barrier against paracellular permeation of lumenal antigens. Defects in TJ barrier such as increased levels of pore-forming TJ protein CLDN2 (claudin-2) is associated with inflammatory bowel disease. We have previously reported that starvation-induced macroautophagy/autophagy enhances the TJ barrier by degrading pore-forming CLDN2.

Matrix Metalloproteinase MMP-12 Promotes Macrophage Transmigration Across Intestinal Epithelial Tight Junctions and Increases Severity of Experimental Colitis.

Background And Aims: Matrix metalloproteinases [MMPs] play an important role in extracellular matrix regulation during cell growth and wound healing. Increased expression of MMP-12 [human macrophage elastase] has been reported in inflammatory bowel disease [IBD] which is characterised by the loss of epithelial tight junction [TJ] barrier function and an excessive inflammatory response. The aim of this study was to investigate the role of MMP-12 in intestinal TJ barrier function and inflammation.

The mRNA-binding protein IGF2BP1 maintains intestinal barrier function by up-regulating occludin expression.

Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) is an mRNA-binding protein that has an oncofetal pattern of expression. It is also expressed in intestinal tissue, suggesting that it has a possible role in intestinal homeostasis. To investigate this possibility, here we generated Villin CreERT2:Igf2bp1flox/flox mice, which enabled induction of an IGF2BP1 knockout specifically in intestinal epithelial cells (IECs) of adult mice.

Intestinal epithelial tight junction barrier regulation by autophagy-related protein ATG6/beclin 1.

A defective tight junction (TJ) barrier is a key pathogenic factor for inflammatory bowel disease. Previously, we have shown that autophagy, a cell survival mechanism, enhances intestinal epithelial TJ barrier function. Autophagy-related protein-6 (ATG6/beclin 1), a key protein in the autophagy pathway, also plays a role in the endocytic pathway.