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.
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Research Article Immunology

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

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Figure 6

IL-22 administration overcomes CS-mediated inhibition of epithelial proliferation ex vivo and in vivo.

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IL-22 administration overcomes CS-mediated inhibition of epithelial prol...
(A) Representative Western blot of SI organoids treated with or without MP (10 μM) for 24 hours, followed by treatment with rmIL-22 (5 ng/mL) for 2 hours. (B–D) Representative images and frequency and size of SI organoids cultured with or without MP and rmIL-22 (0.5 ng/mL) for 5 days (n = 3–4 wells per group). Scale bars: 200 μm. (E and F) Representative images and size of human SI organoids cultured with or without MP (10 μM) and rhIL-22 (10 ng/mL) for 6 days (n = 6 wells per group). Scale bars: 1,000 μm. (G and H) qPCR to determine Cdkn1a and Ccna2 expression in organoids cultured with or without MP (10 μM) and rmIL-22 (1 ng/mL) for 3 days (n = 3 wells per group). (I and J) B6 mice treated or not with MP (2 mg/kg i.p. daily) with or without F-652 (100 μg/kg s.c. every other day). Representative images and ileal crypt frequency and height on day 7 (n = 8–12 independent sections per group). Scale bars: 50 μm. (K–M) WT B6 mice were treated or not with MP (2 mg/kg i.p. daily) with or without F-652 (100 μg/kg s.c. every other day), starting 72 hours after TBI. Representative images, ileal crypt frequency and height, and Ki67+ cell frequency (n = 8–23 independent sections per group) on day 7. Scale bars: 50 μm. (N–Q) B6-into-BALB/c transplantation of BM with or without T cells. Recipients were treated or not with MP (2 mg/kg i.p. daily) with or without F-652 (100 μg/kg s.c. every other day), starting on day 7 after BMT. Ileal crypt frequency and height and Ki67+ and Olfm4+ cell frequency (n = 14–31 independent sections per group) on day 14 after BMT. Scale bars: 50 μm. Data are representative of at least 2 independent experiments or were combined from 2 experiments (K–Q). *P < 0.05, **P < 0.01, and ***P < 0.001, by 2-tailed t test or 1-way ANOVA.