Mécanismes régulateurs de la perméabilité des jonctions serrées épithéliales du tube digestif

The intercellular tight junctions of epithelial of gut epithelial cell are multiple protein structures (occludin, claudins, JAM). These TJ proteins are linked to the epithelial cell cytoskeleton filaments in particular the apical ring of actinomyosin through different connecting structures such as ZO1-ZO3. In physiological situation, this intercellular filter offers the passage of molecules up to 1 KD while in pathological states, it can permit the passage of macromolecules of 40 KD and in some instances bacterial translocation. These periods of “open” TJs mainly result from cytoskeleton contraction linked to phosphorylation of myosin light chain (MLC) by MLC kinase (MLCK). Activation of MLCK may be triggered by receptors located on both apical and basolateral membrane of epithelial cells through different signaling pathways (such as Rho kinase, MAPKK, PLC) resulting from change in shape and organization of TJ proteins. This phenomenon is involved in many pathologies of the gut including Infammatory Bowel Disease (IBD), Irritable Bowel Syndrome (IBS), celiac disease and infectious gastroenteritis. Protease-Activated Receptors (PARs) and particularly PAR-2 and PAR-4 located on apical membrane of epithelial cells, are involved in IBS and IBD respectively. The increased permeability is responsible for the activation of the local immune system given rise to sensitization of mechanosensitive afferent neurons generating abdominal pain. This state of sensitization also depends upon the activation of mucosal mast cells that can be triggered by endogenous factors. Some recent data also support the hypothesis that alimentary nutrients and some ingested xenobiotics contribute to such abnormalities of intestinal permeability and may favor in turn bacterial translocation of commensal flora.