Abstract
Crohn’s disease (CD) has an altered intestinal barrier function, yet the underlying mechanisms remain to be disclosed. The tricellular tight junction protein tricellulin is involved in the maintenance of the paracellular macromolecule barrier and features an unchanged expression level in CD but a shifted localization. As angulins are known to regulate the localization of tricellulin, we hypothesized the involvement of angulins in CD. Using human biopsies, we found angulin-1 was downregulated in active CD compared with both controls and CD in remission. In T84 and Caco-2 monolayers, leptin, a cytokine secreted by fat tissue and affected in CD, decreased angulin-1 expression. This effect was completely blocked by STAT3 inhibitors, Stattic and WP1066, but only partially by JAK2 inhibitor AG490. The effect of leptin was also seen at a functional level as we observed in Caco-2 cells an increased permeability for FITC-dextran 4 kDa indicating an impaired barrier against macromolecule uptake. In conclusion, we were able to show that in active CD angulin-1 expression is downregulated, which leads to increased macromolecule permeability and is inducible by leptin via STAT3. This suggests that angulin-1 and leptin secretion are potential targets for intervention in CD to restore the impaired intestinal barrier.
Highlights
Crohn’s disease (CD) is a chronic idiopathic relapsing and remitting gastrointestinal condition with a climbing prevalence in western countries and an increasing incidence in developing regions [1,2]
We focused on analyzing the expression of tricellular TJ (tTJ) proteins in CD and found angulin-1 to be downregulated
Simple endoscopic score for CD (SES-CD) is a simplified scoring system that is commonly used to evaluate the endoscopic presentation of CD patients, the items of which includes mucosal ulcers, surface involved by CD or ulceration, and the presence of narrowing [36]
Summary
Crohn’s disease (CD) is a chronic idiopathic relapsing and remitting gastrointestinal condition with a climbing prevalence in western countries and an increasing incidence in developing regions [1,2]. Environmental influence and microbiota, the pathogenesis of CD might result from miscommunication between intestinal epithelial cells and the immune system [3]. Hypertrophic and hyperplastic adipocytes could lead to cell apoptosis, hypoxia, macrophages infiltration, and proinflammatory cytokines releasement (i.e., TNF-α, IL-1β and IL-6) [4]. In CD, a characteristic thickened mesenteric fat tissue adjacent to inflamed intestinal segments was described [5]. This “creeping fat” could be an important source of additional cytokine release. An increasing amount of leptin could lead to the damage of the epithelial wall and the infiltration of neutrophils [6,7,8]
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