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.
Highlights
Epithelial dysfunction and crypt destruction are defining features of inflammatory bowel disease (IBD)
Using humanized mouse intestinal organoids, a humanized in vivo IBD model, and human intestinal organoids, we uncover an essential role for LRH-1 in intestinal epithelial homeostasis and cell survival, which mitigates inflammatory injury
In order to investigate the role of LRH-1 in gut epithelia, LRH-1 expression and the effects of its deletion were determined in mouse intestinal organoids
Summary
Transcriptional profiling of Lrh1fl/fl and Lrh1IEC-KO intestinal organoids revealed significant gene changes in cell survival and apoptosis pathways (Fig. 1d, e), suggesting a role for LRH-1 in intestinal epithelial homeostasis and viability Consistent with this notion, a marked increase in activated Caspase 3 (Casp-3) was observed in the intestinal crypt domain of Lrh1IEC-KO organoids, which was further exacerbated by TNFα (Fig. 1f, g). Rather than observing an expansion of EECs, as previously described with Notch inhibition[23,24], the number of enterochromaffin cells, a representative sub-population of EEC cells, was significantly reduced in Lrh1IEC-KO intestine (Fig. 2c, d), as were levels of EECspecific transcripts (Fig. 1d) These data imply that LRH-1 is necessary for maintenance of Notch signaling and cell survival and for proper allotment of intestinal epithelial cell types. Expressing hLRH-1 resulted in upregulation of known downstream targets including Shp, Cyp11a1, and Cyp11b1 as well as
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