Corticosteroids impair epithelial regeneration in immune-mediated intestinal damage Journal Article
| Authors: | Arnhold, V.; Chang, W. Y.; Jansen, S. A.; Thangavelu, G.; Calafiore, M.; Vinci, P.; Fu, Y. Y.; Ito, T.; Takashima, S.; Egorova, A.; Kuttiyara, J.; Perlstein, A.; van Hoesel, M.; Liu, C.; Blazar, B. R.; Lindemans, C. A.; Hanash, A. M. |
| Article Title: | 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. © 2024, Arnhold et al. |
| Keywords: | survival; controlled study; nonhuman; drug megadose; ki 67 antigen; cell proliferation; medical decision making; animal cell; mouse; animal; metabolism; animals; mice; animal tissue; protein bcl 2; stat3 protein; apoptosis; gene expression; animal experiment; animal model; tissue regeneration; steroid; retrospective study; radiation response; regeneration; prednisolone; immune response; glycogen synthase kinase 3beta; graft versus host reaction; methylprednisolone; cyclin dependent kinase inhibitor 1a; corticosteroid; hermes antigen; graft vs host disease; ex vivo study; intestine; intestines; intestine injury; intestine mucosa; cyclin a2; steroids; intestinal mucosa; l selectin; adrenal cortex hormones; intestine epithelium; intestinal stem cell; ruxolitinib; humans; human; male; article; single cell rna seq; intestinal organoid |
| Journal Title: | Journal of Clinical Investigation |
| Volume: | 134 |
| Issue: | 7 |
| ISSN: | 0021-9738 |
| Publisher: | American Society for Clinical Investigation |
| Date Published: | 2024-04-01 |
| Start Page: | e155880 |
| Language: | English |
| DOI: | 10.1172/jci155880 |
| PUBMED: | 38349762 |
| PROVIDER: | scopus |
| PMCID: | PMC10977993 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding author is Alan Hanash -- Source: Scopus |
