Epithelial deletion of the glucocorticoid receptor (Nr3c1) protects the mouse intestine against experimental inflammation

María Arredondo-Amador, Carlos J. Aranda, Borja Ocón, Raquel González, Olga Martínez-Augustin, Fermín Sánchez de Medina

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Background and Purpose: Glucocorticoids are the first line treatment for the flare-ups of inflammatory bowel disease, but they have significant limitations. The objective of this study is to investigate whether glucocorticoid epithelial actions contribute to such limitations. Experimental Approach: Intestinal epithelium glucocorticoid receptor knockout mice (Nr3c1ΔIEC) received dextran sulfate sodium (DSS) to induce colitis. Inflammatory status was assessed by morphological and biochemical methods, and corticoid production was measured in colonic explants. Some mice were administered budesonide. Key Results: After 7 days of DSS Nr3c1ΔIEC, mice exhibited 23.1% lower disease activity index (DAI) and 37% lower diarrheal score than WT mice, with decreased weight loss in days 5–7 of colitis, attenuated tissue damage, reduced colonic expression of S100A9 and STAT3 phosphorylation, and a better overall state. Ki67 immunoreactivity was increased at the crypt base, indicating enhanced epithelial proliferation. Mice administered budesonide (6 μg·day−1 PO) showed modest antiinflammatory effects but increased weight loss, which was prevented in knockout mice. Epithelial deletion of the glucocorticoid receptor also protected mice in a protracted colitis protocol. Conversely, knockout mice presented a worse status compared to the control group at 1 day post DSS. In a separate experiment, colonic corticosterone production was shown to be significantly increased in knockout mice at 7 days of colitis but not at earlier stages. Conclusions and Implications: The intestinal epithelial glucocorticoid receptor has deleterious effects in experimental colitis induced by DSS, probably related to inhibition of epithelial proliferative responses leading to impaired wound healing and reduced endogenous corticosterone production.

Original languageEnglish
Pages (from-to)2482-2495
Number of pages14
JournalBritish Journal of Pharmacology
Volume178
Issue number12
DOIs
StatePublished - Jun 2021
Externally publishedYes

Keywords

  • DSS colitis
  • budesonide
  • corticosterone
  • epithelial proliferation
  • steroidogenesis

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