LRH-1 mitigates intestinal inflammatory disease by maintaining epithelial homeostasis and cell survival

• DOI: 10.1038/s41467-018-06137-w
• Publication Date: 2018-09-27T11:27:48Z
• Authors: James R. Bayrer; Hongtao Wang; Roy Nattiv; Miyuki Suzawa; Hazel S. Escusa; Robert J. Fletterick; Ophir D. Klein; David D. Moore; Holly A. Ingraham
• Keywords: Intestinal epithelium; Homeostasis; Organoid; Intestinal mucosa

Epithelial dysfunction and crypt destruction are defining features of inflammatory bowel disease (IBD). However, current IBD therapies targeting epithelial lacking. The nuclear receptor LRH-1 (NR5A2) is expressed in intestinal epithelium thought to contribute renewal. Here we show that maintains health protects against damage. Knocking out murine organoids reduces Notch signaling, increases cell death, distorts the cellular composition epithelium, weakens barrier. Human (hLRH-1) rescues integrity when overexpressed, mitigates damage human organoids, including those derived from patients. Finally, hLRH-1 greatly severity T-cell-mediated colitis. Together with failure a ligand-incompetent mutant protect TNFα-damage, these findings provide compelling evidence mediates homeostasis an attractive target for disease.