NOVEL CONTRIBUTIONS OF CLAUDIN-4 TO EPITHELIAL BARRIER REGULATION AND COLITIS. (22nd January 2022)

• Record Type: Journal Article
• Authors: Shashikanth, Nitesh; Liu, Yunuo; Xing, Tiaosi; Turner, Jerrold
• Is Part Of: Inflammatory bowel diseases. Volume 28(2022)Supplement 1
• Page Start: S51
• Page End: S52
• Publication Date: 2022-01-22
• Subjects: Inflammatory bowel diseases -- Periodicals; Colitis, Ulcerative -- Periodicals; Crohn Disease -- Periodicals; Inflammatory Bowel Diseases -- Periodicals; 616.344
• DOI: 10.1093/ibd/izac015.081
• Languages: English
• ISSNs: 1078-0998

Abstract

Abstract: Intestinal barrier dysfunction is linked to human IBD and contributes to progression of experimental, immune-mediated colitis. Claudin family tight junction proteins are critical determinants of epithelial paracellular permeability and barrier function. Expression of one of these, claudin-2, a pore-forming claudin, is specifically upregulated in IBD. We have shown that claudin-2 overexpression or, conversely, channel inhibition, augment or attenuate, respectively, immune-mediated colitis severity. We sought to understand claudin contributions to barrier function using in vitro and in vivo models. Claudin-4 overexpression has been shown to reduce cation permeability in vitro, leading to the conclusion that this protein is a barrier-forming claudin. We found, however, that, in the absence of claudin-2 expression, neither knockout nor overexpression of claudin-4 affected barrier function. Instead, claudin-4 specifically suppressed claudin-2 pore function by destabilizing claudin-2 polymers and disrupting claudin-2 anchoring at the tight junction. Thus, claudin-4 is not barrier-forming but is the first pore-regulating claudin. Together with observations that claudin-2 exacerbates colitis in vivo and that claudin-4 antagonizes claudin-2 function in vitro led us to hypothesize that intestinal epithelial claudin-4 knockout would exacerbate colitis. Knockout mice were, however, protected from both immune-mediated and DSS-induced chemical colitis. Conversely, transgenic claudin-4 overexpression exacerbated colitis. Preliminary in vitro studies suggest that claudin-4 may limit collective migration and epithelial wound repair. As a whole, our studies require a reconsideration of claudin functional classifications and reveal unanticipated contributions of claudin-4 to barrier regulation and epithelial wound repair. The relationship between these functions and claudin-4 downregulation in human IBD remains to be explored.