Abstract
While apoptosis plays a significant role in intestinal homeostasis, it can also be pathogenic if overactive during recovery from inflammation. We recently reported that microRNA-24-3p (miR-24-3p) is elevated in the colonic epithelium of ulcerative colitis patients during active inflammation, and that it reduced apoptosis in vitro. However, its function during intestinal restitution following inflammation had not been examined. In this study, we tested the influence of miR-24-3p on mucosal repair by studying recovery from colitis in both novel miR-24-3p knockout and miR-24-3p-inhibited mice. We observed that knockout mice and mice treated with a miR-24-3p inhibitor had significantly worsened recovery based on weight loss, colon length, and double-blinded histological scoring. In vivo and in vitro analysis of miR-24-3p inhibition in colonic epithelial cells revealed that inhibition promotes apoptosis and increases levels of the pro-apoptotic protein BIM. Further experiments determined that silencing of BIM reversed the pro-apoptotic effects of miR-24-3p inhibition. Taken together, these data suggest that miR-24-3p restrains intestinal epithelial cell apoptosis by targeting BIM, and its loss of function is detrimental to epithelial restitution following intestinal inflammation.
Highlights
Ulcerative colitis (UC) is a chronic inflammatory disease of the colon and rectum
RESULTS miR-24-3p knockout mice exhibit reduced mucosal repair after colitis To determine whether miR-24-3p regulates the recovery from colitis we first created a knockout mouse
Starting on day 5, mice were placed on water for an additional 5 days to enable the onset of mucosal repair mechanisms (Fig. 1C)
Summary
Ulcerative colitis (UC) is a chronic inflammatory disease of the colon and rectum. For patients with UC, achieving and maintaining mucosal healing is an important predictor of sustained disease remission [1]. Following a flare of inflammation, mucosal repair requires intestinal epithelial cells to proliferate, migrate, and resist apoptosis [2,3,4]. Molecular pathways such as Wnt and EGFR drive proliferative events [5, 6] while integrins regulate migration into the wound [7, 8]. Various studies over the past 15 years have profiled UC patient tissue for alterations in microRNA expression [10]. These experiments have uncovered a number of specific microRNAs with functional significance for the pathophysiology of UC. We hypothesized that genetically removing or inhibiting miR-24-3p would enhance epithelial cell death and reduce mucosal repair after inflammation
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