Investigating the role of the tight junction protein claudin-4 in experimental IBD
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Abstract
Intestinal bowel disease (IBD) comprises several chronic disorders that can cause inflammation in the intestines. Defects in the epithelial barrier function have been observed to play a vital role in IBD pathology. Claudins are a family of integral membrane proteins that comprise tight junctions and are critical determinants of epithelial barrier function. The pore-forming claudins regulate paracellular flux by forming charge and size-selective pores, e.g., claudin-2 and -15. On the other hand, so-called barrier-forming claudins, such as claudin-4, are supposed to function by forming a fence/seal at tight junctions. Previous studies have shown that unregulated paracellular permeability in mice overexpressing a pore-forming claudin-2 results in severe clinical disease in an experimental IBD model, whereas claudin-2 KO mice are protected. However, the role of barrier-forming claudins like claudin-4 in an experimental IBD setting has not been well examined. In this study, two kinds of experimental IBD models- chronic (T cell transfer) and acute (DSS) models to study IBD in mice. As claudin-4 is a barrier-forming claudin, we hypothesized that conditional claudin-4 knockout promotes intestinal damage and induces colitis. Surprisingly, we found that claudin0-4 KKO had a protective effect on the disease severity compared to WT or claudin-4 overexpressing transgenic mice. These results show that the tight junction barrier enhancing functions of claudin-4 might be secondary to its effect on epithelial wound repair.