Corticosteroids impair epithelial regeneration in immune-mediated intestinal damage.

Abstract

Corticosteroid treatment (CST) failure is associated with poor outcomes for patients with gastrointestinal (GI) graft-versus-host disease (GVHD). CST is intended to target the immune system, but the glucocorticoid receptor (GR) is widely expressed, including within the intestines, where its effects are poorly understood. Here, we report that corticosteroids (CS) directly targeted intestinal epithelium, potentially worsening immune-mediated GI damage. CS administered to mice in vivo and intestinal organoid cultures ex vivo reduced epithelial proliferation. Following irradiation, immediate CST mitigated GI damage but delayed treatment attenuated regeneration and exacerbated damage. In a murine steroid-refractory (SR) GVHD model, CST impaired epithelial regeneration, worsened crypt loss, and reduced intestinal stem cell (ISC) frequencies. CST also exacerbated immune-mediated damage in organoid cultures with SR, GR-deficient T cells or IFN-γ. These findings correlated with CS-dependent changes in apoptosis-related gene expression and STAT3-related epithelial proliferation. Conversely, IL-22 administration enhanced STAT3 activity and overcame CS-mediated attenuation of regeneration, reducing crypt loss and promoting ISC expansion in steroid-treated mice with GVHD. Therefore, CST has the potential to exacerbate GI damage if it fails to control the damage-inducing immune response, but this risk may be countered by strategies augmenting epithelial regeneration, thus providing a rationale for clinical approaches combining such tissue-targeted therapies with immunosuppression.

• Authors: Viktor Arnhold, Winston Y Chang, Suze A Jansen, Govindarajan Thangavelu, Marco Calafiore, Paola Vinci, Ya-Yuan Fu, Takahiro Ito, Shuichiro Takashima, Anastasiya Egorova, Jason Kuttiyara, Adam Perlstein, Marliek van Hoesel, Chen Liu, Bruce R Blazar, Caroline A Lindemans, Alan M Hanash
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 134 Issue 7 (Feb 13 2024) ISSN: 1558-8238 [Electronic] United States
• PMID: 38349762 (Publication Type: Journal Article)

Chemical References

• Adrenal Cortex Hormones
• Steroids

Topics

• Humans
• Mice
• Animals
• Intestines
• Intestinal Mucosa (metabolism)
• Adrenal Cortex Hormones
• Graft vs Host Disease (drug therapy, metabolism)
• Steroids (metabolism)
• Regeneration (radiation effects)