Corticosteroids impair epithelial regeneration in immune-mediated intestinal damage
Viktor Arnhold, … , Caroline A. Lindemans, Alan M. Hanash
Viktor Arnhold, … , Caroline A. Lindemans, Alan M. Hanash
Published February 13, 2024
Citation Information: J Clin Invest. 2024;134(7):e155880. https://doi.org/10.1172/JCI155880.
View: Text | PDF
Research Article Immunology Article has an altmetric score of 5

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

×

Figure 3

CS reduce the proliferation of murine and human organoid cells.

Options: View larger image (or click on image) Download as PowerPoint
CS reduce the proliferation of murine and human organoid cells. (A) Quan...
(A) Quantifications of intracellular Ki67-DAPI cell-cycle analysis in live organoid cells cultured with or without MP (10 μM) for 5 days (n = 4 wells per group). (B) Flow cytometry plots and quantification of intracellular Ki67-DAPI cell-cycle analysis in GFP+ cells from Lgr5-GFP SI organoids cultured with or without MP (10 μM) for 5 days (n = 4 wells per group). (C) Flow cytometry plots and quantification of GFP+ cell fractions from Lgr5-GFP SI organoids cultured with or without MP (10 μM) for 5 days (n = 3 wells per group). (D) RT-qPCR to determine Cdkn1a, Ccna2, and Ccnb1 expression in organoids derived from SI crypts cultured in ENR or ISC colonies (ISCC) cultured in ENR supplemented with histone deacetylase and GSK3β inhibition (CV) with or without MP (10 μM) for 4 days (n = 3 wells per group). (E and F) Flow cytometry plots and quantification of CTV in human SI organoids cultured with or without MP (10 μM) for 5 days (n = 6 donors per group). *P < 0.05, **P < 0.01, and ***P < 0.001, by 2-tailed t test or 1-way ANOVA. Data are representative of at least 2 independent experiments.