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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Categories: 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 1

Adrenalectomy induces atrophic gastritis, mucous cell metaplasia, and chronic inflammation of the gastric corpus.

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Adrenalectomy induces atrophic gastritis, mucous cell metaplasia, and ch...
Stomachs were collected from mice euthanized 2 months after sham surgery (Sham-ADX) or adrenalectomy (ADX). (A) Representative immunostaining of the gastric corpus lesser curvature probed for the glucocorticoid receptor (GR, green); F-actin was labeled with phalloidin (red). (B) Representative whole-mount images of mouse stomachs opened along the greater curvature. Arrows indicate the location of lesions, which develop after adrenalectomy. (C) Micrographs of H&E-stained sections of the gastric corpus lesser curvature. (D–E) Immunostaining of stomach sections from the lesser curvature stained for SIGLECF (eosinophils, green, D) or CD68 (macrophages, green, E). Nuclei were labeled with DAPI (blue). Scale bars: 100 μm (inset in A: 25 μm); n = 8 mice/group for all experiments.