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 1

CS treatment reduces epithelial proliferation in vivo.

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CS treatment reduces epithelial proliferation in vivo. (A) Survival perc...
(A) Survival percentage, GHVD clinical score, and relative weights of B6-into-BALB/c BMT recipients, with or without prednisolone (1, 3, or 6 mg/kg i.p. daily from day 1 to day 28 after BMT); n = 13 (BM only), n = 24 (BM plus T cells, vehicle), n = 8 (BM plus T cells, 1 mg/kg), n = 8 (BM plus T cells, 3 mg/kg), and n = 16 (BM plus T cells, 6 mg/kg) mice per group. Data were combined from 2 independent experiments. (B) UMAP visualization of 12,457 SI epithelial cells from naive WT B6 mice. Left map shows unsupervised clustering based on the expression of known marker genes; right map shows expression of Nr3c1. TPM, transcripts per million. (C) IHC images of GR staining in ileal sections from naive WT mice. Scale bars: 50 μm. (D–H) WT B6 mice were treated with MP (2 mg/kg i.p. daily for 7 days) or vehicle control (Ctrl). Results are representative of 2 experiments. (D) Representative Lgr5-Lacz images and ileal crypt and ISC frequencies (n = 7–9 independent sections per group). Scale bars: 250 μm. (E and F) Representative Lgr5-Lacz SI crypt images and data on ileal crypt height, TA height, and crypt/villus height ratio (n = 8–18 independent sections per group). Scale bars: 50 μm. (G) Ki67 IHC images and Ki67+ cell frequencies (n = 17 independent sections per group). Scale bars: 50 μm. (H) RT-qPCR to determine Cdkn1a expression in ileal tissue (n = 3 mice per group). (I) GSEA of Kyoto Encyclopedia of Genes and Genomes (KEGG) cell-cycle pathway genes in SI epithelial cells from WT mice treated with DEX or vehicle. The nominal P value is shown. *P < 0.05, **P < 0.01, and ***P < 0.001, by log-rank test (A) or 2-tailed t test (D–H).