Essential role of IFN-γ in T cell–associated intestinal inflammation
Yoshihiro Eriguchi, Kiminori Nakamura, Yuki Yokoi, Rina Sugimoto, Shuichiro Takahashi, Daigo Hashimoto, Takanori Teshima, Tokiyoshi Ayabe, Michael E. Selsted, André J. Ouellette
Yoshihiro Eriguchi, Kiminori Nakamura, Yuki Yokoi, Rina Sugimoto, Shuichiro Takahashi, Daigo Hashimoto, Takanori Teshima, Tokiyoshi Ayabe, Michael E. Selsted, André J. Ouellette
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Research Article Gastroenterology Inflammation

Essential role of IFN-γ in T cell–associated intestinal inflammation

Abstract

Paneth cells contribute to small intestinal homeostasis by secreting antimicrobial peptides and constituting the intestinal stem cell (ISC) niche. Certain T cell–mediated enteropathies are characterized by extensive Paneth cell depletion coincident with mucosal destruction and dysbiosis. In this study, mechanisms of intestinal crypt injury have been investigated by characterizing responses of mouse intestinal organoids (enteroids) in coculture with mouse T lymphocytes. Activated T cells induced enteroid damage, reduced Paneth cell and Lgr5+ ISC mRNA levels, and induced Paneth cell death through a caspase-3/7–dependent mechanism. IFN-γ mediated these effects, because IFN-γ receptor–null enteroids were unaffected by activated T cells. In mice, administration of IFN-γ induced enteropathy with crypt hyperplasia, villus shortening, Paneth cell depletion, and modified ISC marker expression. IFN-γ exacerbated radiation enteritis, which was ameliorated by treatment with a selective JAK1/2 inhibitor. Thus, IFN-γ induced Paneth cell death and impaired regeneration of small intestinal epithelium in vivo, suggesting that IFN-γ may be a useful target for treating defective mucosal regeneration in enteric inflammation.

Authors

Yoshihiro Eriguchi, Kiminori Nakamura, Yuki Yokoi, Rina Sugimoto, Shuichiro Takahashi, Daigo Hashimoto, Takanori Teshima, Tokiyoshi Ayabe, Michael E. Selsted, André J. Ouellette

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Figure 9

Aggravated radiation enteropathy and impaired epithelial regeneration induced by IFN-γ.

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Aggravated radiation enteropathy and impaired epithelial regeneration in...
(A) Schematics of the study to determine effects of TBI, IFN-γ, and ruxolitinib on intestinal epithelium in mice. Ileum tissue was collected 48 hours after TBI and analyzed. (B) Representative small intestines of control (C), IFN-γ (I), IFN-γ + ruxolitinib (IR), TBI (T), TBI + IFN-γ (TI), and TBI + IFN-γ + ruxolitinib (TIR) mice are shown. Scale bars: 8 cm. (C) Lengths of small bowels in cohort. Measurements from 2 experiments were combined and presented as mean ± SD; control group, n = 4; TIR, n = 7; remaining groups, n = 6. (D–G) Quantification of crypt numbers per ileum circumference section at 48 hours after TBI. Whole (D), cryptdin-1+ (E), Lgr5-GFP+ (F), and Olfm4+ (G) crypts were counted in 2 ileum circumference sections of 3 different Lgr5-EGFP-ires-creERT2 mice from each group. Data are from 2 separate experiments and show mean ± SD. (H and I) qRT-PCR analyses were performed to quantify mRNAs coding for lineage-specific markers, niche factors, and requisite lineage-determining transcription factors in whole terminal ileum tissue. Data from 2 separate experiments were combined and are shown as mean ± SEM; TIR group, n = 7; all other groups, n = 6 biological replicates. Tukey’s multiple comparisons test was used to compare each cohort. Mean values of data in C–G and statistical results in C–I are presented in Supplemental Tables 2–4.