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

James R. Bayrer, Hongtao Wang, Roy Nattiv, Miyuki Suzawa, Hazel S. Escusa, Robert J. Fletterick, Ophir D. Klein, David D. Moore () and Holly A. Ingraham ()
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James R. Bayrer: University of California San Francisco
Hongtao Wang: Baylor College of Medicine
Roy Nattiv: University of California San Francisco
Miyuki Suzawa: University of California San Francisco
Hazel S. Escusa: University of California San Francisco
Robert J. Fletterick: University of California San Francisco
Ophir D. Klein: University of California San Francisco
David D. Moore: Baylor College of Medicine
Holly A. Ingraham: University of California San Francisco

Nature Communications, 2018, vol. 9, issue 1, 1-10

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

Date: 2018
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DOI: 10.1038/s41467-018-06137-w

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