Abstract
Autophagy is an intracellular degradation pathway and is considered to be an essential cell survival mechanism. Defects in autophagy are implicated in many pathological processes, including inflammatory bowel disease. Among the innate defense mechanisms of intestinal mucosa, a defective tight junction (TJ) barrier has been postulated as a key pathogenic factor in the causation and progression of inflammatory bowel disease by allowing increased antigenic permeation. The cross-talk between autophagy and the TJ barrier has not yet been described. In this study, we present the novel finding that autophagy enhances TJ barrier function in Caco-2 intestinal epithelial cells. Nutrient starvation-induced autophagy significantly increased transepithelial electrical resistance and reduced the ratio of sodium/chloride paracellular permeability. Nutrient starvation reduced the paracellular permeability of small-sized urea but not larger molecules. The role of autophagy in the modulation of paracellular permeability was confirmed by pharmacological induction as well as pharmacological and genetic inhibition of autophagy. Consistent with the autophagy-induced reduction in paracellular permeability, a marked decrease in the level of the cation-selective, pore-forming TJ protein claudin-2 was observed after cell starvation. Starvation reduced the membrane presence of claudin-2 and increased its cytoplasmic, lysosomal localization. Therefore, our data show that autophagy selectively reduces epithelial TJ permeability of ions and small molecules by lysosomal degradation of the TJ protein claudin-2.
Highlights
How autophagy, a cell survival mechanism, regulates intestinal epithelial tight junction barrier or paracellular permeability is unknown
Autophagy Regulates Paracellular Permeability, and Pharmacologic Induction of Autophagy Enhances the Caco-2 tight junction (TJ) Barrier—To assess the direct role of autophagy and to rule out the possibility that other biological changes induced by starvation caused the increase in the Caco-2 TJ barrier, we examined whether the pharmacological induction of autophagy in normally fed Caco-2 cells was sufficient to cause an enhancement in the caco-2 TJ barrier
Nothing is known about how autophagy regulates intestinal epithelial barrier function that act as the first line of host defense against intestinal luminal antigens and is an important component of innate immunity
Summary
A cell survival mechanism, regulates intestinal epithelial tight junction barrier or paracellular permeability is unknown. Results: Autophagy reduces the paracellular permeability of small solutes and ions via degradation of the pore-forming tight junction protein claudin-2. Conclusion: Autophagy enhances tight junction barrier function by targeting claudin-2. Among the innate defense mechanisms of intestinal mucosa, a defective tight junction (TJ) barrier has been postulated as a key pathogenic factor in the causation and progression of inflammatory bowel disease by allowing increased antigenic permeation. Consistent with the autophagy-induced reduction in paracellular permeability, a marked decrease in the level of the cation-selective, pore-forming TJ protein claudin-2 was observed after cell starvation. Our data show that autophagy selectively reduces epithelial TJ permeability of ions and small molecules by lysosomal degradation of the TJ protein claudin-2
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