Protease‐activated receptor 2 and gut permeability: a review

Abstract

Digestive tract proteases are best known for their proteolytic activity in the digestion of alimentary proteins. However, during the last decade, a possible role of proteases as signalling molecules has been emphasized with the discovery of a novel class of G-protein coupled receptors located on cell membranes that may be activated by proteolytic cleavage of their N-terminal extracellular domain. Type 2 protease-activated receptors (PAR-2) are cleaved by serine-proteases such as trypsin and tryptase. PAR-2 is present in many intestinal cell types and particularly on epithelial cells. Multiple functions have been demonstrated in the gut for PAR-2, including epithelial permeability, mainly the intercellular permeability that is of paramount importance in the equilibrium between the external milieu (digestive contents) and the submucosal immune system. Alterations of both tissue and luminal levels of proteases or serine-protease activity may affect gut permeability and subsequently the immune status of the mucosa. Activation of PAR-2 on epithelial cells may directly affect cytoskeleton contraction by triggering phosphorylation of myosin light chain with subsequent changes in tight junction permeability. Enhanced fecal protease level has been recently reported in both organic (ulcerative colitis) and functional (irritable bowel syndrome) intestinal disorders and may play a role in the pathogenesis of such diseases.

Identification of human zonulin, a physiological modulator of tight junctions, as prehaptoglobin-2

“…The role of both EGFR and PAR 2 in regulating epithelial permeability has been previously reported (33,34). However, our study provides previously undescribed evidence that the 2 receptors work cooperatively to regulate small intestine permeability.…”

Protease-Activated Receptor-2 Induces Myofibroblast Differentiation and Tissue Factor Up-Regulation during Bleomycin-Induced Lung Injury

“…Indeed, epithelial barrier dysfunction contributes to fibrosis 38 -40 and PAR-2 activation seems to increase epithelial permeability in different organs. [41][42][43] In the lung, PAR-2 activation causes a rapid and transient increase in permeability of airway epithelium that persists for 6 to 10 minutes. Our results support and extend these observations by showing that longer stimulation results in a persistent PAR-2Ϫdependent increase in epithelial permeability (Supplemental Figure S3, http://ajp.amjpathol.org/).…”

Presence of commensal house dust mite allergen in human gastrointestinal tract: a potential contributor to intestinal barrier dysfunction

“…Moreover, we and others have shown that the disruption of epithelial barrier in IBD and IBS is attributed to destruction of ZO-1 and Occludin-1 TJs 1 2 14–18. The mechanisms proposed include elevated luminal cysteine19 and serine20 protease activity resulting in direct TJ protein destruction and/or indirect activation of PAR-2 14 21 22. Using experimental models of colitis, PAR-2 antagonist have been shown to be effective in ameliorating IBD-like pathology and symptoms;18 21 22 however their effect remains to be tested in humans.…”