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 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 Article has an altmetric score of 3

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 8

Endogenous glucocorticoids are required to maintain gastric homeostasis.

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Endogenous glucocorticoids are required to maintain gastric homeostasis....
Under steady-state conditions, endogenous glucocorticoids suppress the expression of proinflammatory mediators in the gastric corpus. Loss of endogenous glucocorticoids results in the production of proinflammatory mediators, leading to infiltration of circulating monocytes and eosinophils. Infiltrating CX3CR1+ monocytes exhibit pathogenic activation due to disrupted glucocorticoid signaling, and damage the gastric epithelium, leading to SPEM development. Over the course of weeks, parietal cells are lost and the gastric gland becomes predominately filled with metaplastic cells which over time may create a favorable environment for the evolution of gastric adenocarcinoma.