EPITHELIAL WNT SIGNALING DRIVES THE PROGRESSION OF DSS-INDUCED COLITIS IN MURINE MODEL

Abstract

Ulcerative colitis (UC) is a complex disease that involves a dysregulated immune response. Increased intestinal permeability resulting in inflammation is well established in the study of colitis. In addition, Wnt/ß-signaling (also referred to as Wnt signaling) is a crucial inflammatory pathway in the intestinal mucosa and it plays a key role in epithelial stem maintenance, epithelial homeostasis, and regeneration. However, the mechanisms behind epithelial barrier dysfunction and tight-junction-related proteins during progression of colitis are not very clear. TMEM79 (also called MATTRIN) has been identified as a specific antagonist of Wnt signaling, though the specific role of TMEM79 in colitis remains unclear.

In this study, I use TMEM79-deficient (TMEM79-/-) mice and TMEM79 control (TMEM79+/-) mice to investigate the role of TMEM79 in colitis. I demonstrate that TMEM79 deficiency in mice not only enhances baseline intestinal barrier permeability and dysregulation of tight junction proteins but also exacerbates colonic injury induced by dextran sulfate (DSS). Notably, greater severity of colitis on day 6 of DSS exposure was observed in TMEM79-/- mice compared to TMEM79+/- mice, as shown by significant reduction of intestinal proliferation and body weight loss, reduced expression of intestinal epithelial cytokeratin 20 (also referred to as keratin 20) and tight-junction-related proteins claudins 2 & 7, higher diseases activity score (DAI), and shorter colons in DSS-treated TMEM79-/- mice. To my knowledge, this is the first study to show TMEM79 is crucial in intestinal homeostasis and repair, thus associating it in the pathogenesis of colitis.