Mast Cell Tryptase Controls Paracellular Permeability of the Intestine

Abstract

cleavage. When applied to the basolateral surface of colonocytes, PAR 2 agonists and mast cell supernatant decreased transepithelial resistance, increased transepithelial flux of macromolecules, and induced redistribution of tight junction ZO-1 and occludin and perijunctional F-actin. When mast cells were co-cultured with colonocytes, mast cell degranulation increased paracellular permeability of colonocytes. This was prevented by a tryptase inhibitor. We determined the role of ERK1/2 and of ␤-arrestins, which recruit ERK1/2 to PAR 2 in endosomes and retain ERK1/2 in the cytosol, on PAR 2 -mediated alterations in permeability. An ERK1/2 inhibitor abolished the effects of PAR 2 agonist on permeability and redistribution of F-actin. Downregulation of ␤-arrestins with small interfering RNA inhibited PAR 2 -induced activation of ERK1/2 and suppressed PAR 2 -induced changes in permeability. Thus, mast cells signal to colonocytes in a paracrine manner by release of tryptase and activation of PAR 2 . PAR 2 couples to ␤-arrestin-dependent activation of ERK1/2, which regulates reorganization of perijunctional F-actin to increase epithelial permeability. These mechanisms may explain the increased epithelial permeability of the intestine during stress and inflammation.

Mast Cells and Irritable Bowel Syndrome: From the Bench to the Bedside

“…63,64 Furthermore, PAR2 may induce the activation of extracellular signal-related kinase 1/2 (ERK1/2) and phosphorylation of myosin light chain kinase, which regulates reorganization of F-actin and cytoskeleton and redistribution of tight junction, to increase epithelial permeability. 63,65 Other MC mediators such as interferon-γ, tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-4, IL-13, and prostaglandin E2 also have destructive effects on both trans-and paracellular permeability. 65 More recently, further investigations were carried out to map the regulation of permeability in follicle-associated epithelium (FAE), which is a specialized epithelium that covers Peyer's patches, and contain microfold cells that are dedicated to sampling antigens and bacteria from the lumen and transporting them to the underlying immune aggregate in the intestinal mucosa.…”

“…61,62 Numerous evidence showed a positive relationship between the number of mucosal MCs and intestinal permeability, 61 and the MC-derived tryptase was well identified as a key factor disrupts the intestinal barrier. 63 MC tryptase cleaves PAR2 on colonocytes to increase paracellular permeability by acting on intercellular apical junction complex, which mainly consists of the tight junctions such as claudins, occludin, zonula occludens, junctional adhesion molecule, and the adherens junction such as E-cadherin. 63,64 Furthermore, PAR2 may induce the activation of extracellular signal-related kinase 1/2 (ERK1/2) and phosphorylation of myosin light chain kinase, which regulates reorganization of F-actin and cytoskeleton and redistribution of tight junction, to increase epithelial permeability.…”

“…63 MC tryptase cleaves PAR2 on colonocytes to increase paracellular permeability by acting on intercellular apical junction complex, which mainly consists of the tight junctions such as claudins, occludin, zonula occludens, junctional adhesion molecule, and the adherens junction such as E-cadherin. 63,64 Furthermore, PAR2 may induce the activation of extracellular signal-related kinase 1/2 (ERK1/2) and phosphorylation of myosin light chain kinase, which regulates reorganization of F-actin and cytoskeleton and redistribution of tight junction, to increase epithelial permeability. 63,65 Other MC mediators such as interferon-γ, tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-4, IL-13, and prostaglandin E2 also have destructive effects on both trans-and paracellular permeability.…”

Role of Corticotropin-releasing Factor in Gastrointestinal Permeability

“…On the other hand, the tryptase released by mast cells upon activation has been shown to induce TJs disassembly through the activation of proteinase-activated receptor-2 of the epithelial cells. [88][89][90] These receptors can modulate enteric neurotransmission, secretion, motility, epithelial permeability, and visceral sensitivity, and are also known to regulate intestinal inflammation. 91 Anatomical contacts between mast cells and enteric nerve fibers have been demonstrated in the human gastrointestinal mucosa and inflammation multiplies these contacts.…”

Tissue Eosinophilia in a Mouse Model of Colitis Is Highly Dependent on TLR2 and Independent of Mast Cells

“…Mast cells have been shown by a number of groups to modify the epithelial barrier function within the intestine and, when activated, to increase intestinal permeability and fluid loss. [53][54][55][56][57] Such processes could explain enhanced weight loss in mast cell-containing animals.…”