Targeted Epithelial Tight Junction Dysfunction Causes Immune Activation and Contributes to Development of Experimental Colitis

Abstract

Background & Aims-Inflammatory bowel disease (IBD) is a multifactorial disease thought to be caused by alterations in epithelial function, innate and adaptive immunity, and luminal microbiota. The specific role of epithelial barrier function remains undefined, although increased activity of intestinal epithelial myosin light chain kinase (MLCK), which is the primary mechanism of tumor necrosis factor (TNF)-induced barrier dysfunction, occurs in human IBD. We aimed to determine whether in an intact epithelium, primary dysregulation of the intestinal epithelial barrier by pathophysiologically relevant mechanisms can contribute to development of colitis.

Dietary low or excess levels of lipids reduced growth performance, and impaired immune function and structure of head kidney, spleen and skin in young grass carp (Ctenopharyngodon idella) under the infection of Aeromonas hydrophila

“…It was reported that immune response of fish immune organs could generate ROS production which could cause oxidant damage [24] and induce subsequent apoptosis in mice [112]. In this study, low or excess levels of lipids caused apoptosis in the immune organs, which may partly be ascribed to excess ROS production.…”

Role of epithelial cells in the pathogenesis and treatment of inflammatory bowel disease

“…Therefore, proinflammatory cytokine signaling may further enhance the ''leakiness'' of the epithelial layer, which may promote the perpetuation of the local inflammation. However, mice expressing the constitutive active form of MLCK show increased epithelial permeability but does not develop spontaneous colitis in vivo [39], suggesting that leakiness of the epithelial layer alone may not lead to spontaneous development of colitis but requires another ''deleterious hit'' for the onset of the disease [40].…”

“…Also, several cytokines that are produced by the proinflammatory lymphocytes, such as IL-1b or IL-6, may b Goblet cells produce MUC2 or TFF3 and maintain the mucosal layer to sequester gut microbes from the surface of the epithelial layer [39]. Expression of specific ion channels such as Bestrophin2 may support the proper function of the mucus layer [44,45].…”

Bin1: A New Player in IBD Barrier Dysfunction

“…Using transgenic mice that express constitutively active MLCK, Su et al demonstrated that, while insufficient to fully induce experimental colitis alone, TJ defects exacerbated disease in the adoptive transfer colitis model [10]. Other models of barrier disruption, such as dominant negative N-cadherin expression, resulted in spontaneous inflammation [11], further enforcing the link between barrier dysfunction and immune homeostasis.…”