Endogenous glucocorticoids prevent gastric metaplasia by suppressing spontaneous inflammation
Jonathan T. Busada, … , Donald N. Cook, John A. Cidlowski
Jonathan T. Busada, … , Donald N. Cook, John A. Cidlowski
Published March 1, 2019; First published January 17, 2019
Citation Information: J Clin Invest. 2019;129(3):1345-1358. https://doi.org/10.1172/JCI123233.
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Research Article Gastroenterology Immunology

Endogenous glucocorticoids prevent gastric metaplasia by suppressing spontaneous inflammation

Abstract

In the stomach, chronic inflammation causes metaplasia and creates a favorable environment for the evolution of gastric cancer. Glucocorticoids are steroid hormones that repress proinflammatory stimuli, but their role in the stomach is unknown. In this study, we show that endogenous glucocorticoids are required to maintain gastric homeostasis. Removal of circulating glucocorticoids in mice by adrenalectomy resulted in the rapid onset of spontaneous gastric inflammation, oxyntic atrophy, and spasmolytic polypeptide-expressing metaplasia (SPEM), a putative precursor of gastric cancer. SPEM and oxyntic atrophy occurred independently of lymphocytes. However, depletion of monocytes and macrophages by clodronate treatment or inhibition of gastric monocyte infiltration using the Cx3cr1 knockout mouse model prevented SPEM development. Our results highlight the requirement for endogenous glucocorticoid signaling within the stomach to prevent spontaneous gastric inflammation and metaplasia, and suggest that glucocorticoid deficiency may lead to gastric cancer development.

Authors

Jonathan T. Busada, Sivapriya Ramamoorthy, Derek W. Cain, Xiaojiang Xu, Donald N. Cook, John A. Cidlowski

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Figure 2

Endogenous glucocorticoids are required to suppress SPEM and gastric inflammation.

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Endogenous glucocorticoids are required to suppress SPEM and gastric inf...
Analysis of the gastric corpus lesser curvature from mice euthanized 2 months after sham surgery or adrenalectomy or from adrenalectomized mice treated with corticosterone (cort) for 2 months. (A–D) Immunostaining of stomach sections probed for (A) ATP4B (parietal cells, red), GSII lectin (mucous neck cells, pink), and MIST1(chief cells, green), (B) the SPEM marker CD44 variant 9 (green) and GSII lectin (pink), (C) KI67 (green) and CTNNB1 (epithelial cells, red), or for CD45 (leukocytes, green). Nuclei are stained with DAPI (blue). Scale bars: 100 μm (inset in C: 25 μm). (E) Quantitation of the number of parietal cells, chief cells, and proliferating epithelial cells observed per ×20 field within the lesser curvature (n ≥ 6 mice/group). (F) Quantitative RT-PCR of the SPEM marker genes: Wfdc2, Olfm4, and Cftr using RNA isolated from the gastric corpus lesser curvature (n = 4 mice/group). Data are mean ± SD; P values were determined by 1-way ANOVA with post hoc Tukey’s t test. *P ≤ 0.01, **P ≤ 0.001, ***P ≤ 0.0001.