IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v9y2018i1d10.1038_s41467-018-06137-w.html
   My bibliography  Save this article

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

Author

Listed:
  • James R. Bayrer

    (University of California San Francisco
    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
    University of California San Francisco)

  • David D. Moore

    (Baylor College of Medicine)

  • Holly A. Ingraham

    (University of California San Francisco)

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.

Suggested Citation

  • James R. Bayrer & Hongtao Wang & Roy Nattiv & Miyuki Suzawa & Hazel S. Escusa & Robert J. Fletterick & Ophir D. Klein & David D. Moore & Holly A. Ingraham, 2018. "LRH-1 mitigates intestinal inflammatory disease by maintaining epithelial homeostasis and cell survival," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06137-w
    DOI: 10.1038/s41467-018-06137-w
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-018-06137-w
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-018-06137-w?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06137-w. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.