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Nat Commun. 2018 Oct 10;9(1):4055. doi: 10.1038/s41467-018-06137-w.

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

Author information

1
Department of Pediatrics, Division of Gastroenterology, University of California San Francisco, Mission Bay Campus, San Francisco, CA, 94158, USA.
2
Department of Cellular and Molecular Pharmacology, University of California San Francisco, Mission Bay Campus, San Francisco, CA, 94158, USA.
3
Department of Pediatrics, Division of Gastroenterology, Baylor College of Medicine, Houston, TX, 77030, USA.
4
Department of Biochemistry and Biophysics, University of California San Francisco, Mission Bay Campus, San Francisco, CA, 94158, USA.
5
Department of Orofacial Sciences & Program in Craniofacial Biology, University of California San Francisco, Mission Bay Campus, San Francisco, CA, 94158, USA.
6
Department of Pediatrics, Division of Genetics, University of California San Francisco, Mission Bay Campus, San Francisco, CA, 94158, USA.
7
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA. moore@bcm.edu.
8
Department of Cellular and Molecular Pharmacology, University of California San Francisco, Mission Bay Campus, San Francisco, CA, 94158, USA. holly.ingraham@ucsf.edu.

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.

PMID:
30305617
PMCID:
PMC6180039
DOI:
10.1038/s41467-018-06137-w
[Indexed for MEDLINE]
Free PMC Article

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