[HTML][HTML] LRH-1 mitigates intestinal inflammatory disease by maintaining epithelial homeostasis and cell survival
Nature communications, 2018•nature.com
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 …
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 …
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.
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