Journal
NATURE COMMUNICATIONS
Volume 9, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-018-06137-w
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Funding
- Cytometry and Cell Sorting Core at Baylor College of Medicine
- Texas Medical Center Digestive Diseases Center (DDC)
- UCSF Program for Breakthrough Research
- UCSF Resource Allocation Program
- Rainin Foundation
- ADA [7-14-MI-08, R01 DK099722, NDSP-P30 DK097748]
- CIRM [RN3-06525]
- Alkek Foundation
- Robert R.P. Doherty Jr-Welch Chair in Science
- NIH [P30 AI036211, P30 CA125123, S10 RR024574]
- [F32 CA163092]
- [K12 HD072222]
- [K08 DK106577]
- [T32 DK007762]
- [R01 DK085372]
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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 TNF alpha-damage, these findings provide compelling evidence that hLRH-1 mediates epithelial homeostasis and is an attractive target for intestinal disease.
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