Abstract
Intestinal barrier function is required for the maintenance of mucosal homeostasis. Barrier dysfunction is thought to promote progression of both intestinal and systemic diseases. In many cases, this barrier loss reflects increased permeability of the paracellular tight junction as a consequence of myosin light chain kinase (MLCK) activation and myosin II regulatory light chain (MLC) phosphorylation. Although some details about MLCK activation remain to be defined, it is clear that this triggers perijunctional actomyosin ring (PAMR) contraction that leads to molecular reorganization of tight junction structure and composition, including occludin endocytosis. In disease states, this process can be triggered by pro-inflammatory cytokines including tumor necrosis factor-α (TNF), interleukin-1β (IL-1β), and several related molecules. Of these, TNF has been studied in the greatest detail and is known to activate long MLCK transcription, expression, enzymatic activity, and recruitment to the PAMR. Unfortunately, toxicities associated with inhibition of MLCK expression or enzymatic activity make these unsuitable as therapeutic targets. Recent work has, however, identified a small molecule that prevents MLCK1 recruitment to the PAMR without inhibiting enzymatic function. This small molecule, termed Divertin, restores barrier function after TNF-induced barrier loss and prevents disease progression in experimental chronic inflammatory bowel disease.
Highlights
Laboratory of Chemical Biology & Signal Transduction, The Rockefeller University, New York, Laboratory of Mucosal Barrier Pathobiology, Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
The dense forests of microvilli that increase apical surface area and facilitate nutrition absorption [4] are not needed on the basolateral surface, which interacts with adjacent epithelial cells, immune cells, and the basement membrane
Enzymatic myosin light chain kinase (MLCK) inhibition reduced ZO-1 exchange in vivo [84]. This increase in ZO-1 anchoring at the tight junction following MLCK inhibition was mapped to the actin binding region (ABR) of ZO-1 [84]
Summary
Intestinal mucosal surfaces are covered by a single layer of columnar epithelial cells required for absorptive and defensive functions. Microscopy visualization ofstrands distinct microscopy [25,26,27] This an Transmission anastomosing,electron mesh-like network allows of intramembranous regions such as, from apical to basal, tight junctions (zonulae occludens), adherens junctions (zonulae (Figure 1C). Tight junction structure is far more interesting when viewed by freeze-fracture electron microscopy [25,26,27] This reveals an anastomosing, mesh-like network of intramembranous strands (Figure 1C). Lipids must be associated with tight junction structures, these are less well-characterized It is, known that tight junctions are cholesterol- and sphingolipid-rich microdomains and that cholesterol depletion reduces both strand network complexity and paracellular barrier function [32,33,34]
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