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Glucocorticoids and Androgens Protect From Gastric Metaplasia by Suppressing Group 2 Innate Lymphoid Cell Activation.
- Source :
-
Gastroenterology [Gastroenterology] 2021 Aug; Vol. 161 (2), pp. 637-652.e4. Date of Electronic Publication: 2021 May 07. - Publication Year :
- 2021
-
Abstract
- Background & Aims: The immune compartment is critical for maintaining tissue homeostasis. A weak immune response increases susceptibility to infection, but immune hyperactivation causes tissue damage, and chronic inflammation may lead to cancer development. In the stomach, inflammation damages the gastric glands and drives the development of potentially preneoplastic metaplasia. Glucocorticoids are potent anti-inflammatory steroid hormones that are required to suppress gastric inflammation and metaplasia. However, these hormones function differently in males and females. Here, we investigate the impact of sex on the regulation of gastric inflammation.<br />Methods: Endogenous glucocorticoids and male sex hormones were removed from mice using adrenalectomy and castration, respectively. Mice were treated with 5α-dihydrotestosterone (DHT) to test the effects of androgens on regulating gastric inflammation. Single-cell RNA sequencing of gastric leukocytes was used to identify the leukocyte populations that were the direct targets of androgen signaling. Type 2 innate lymphoid cells (ILC2s) were depleted by treatment with CD90.2 antibodies.<br />Results: We show that adrenalectomized female mice develop spontaneous gastric inflammation and spasmolytic polypeptide-expressing metaplasia (SPEM) but that the stomachs of adrenalectomized male mice remain quantitatively normal. Simultaneous depletion of glucocorticoids and sex hormones abolished the male-protective effects and triggered spontaneous pathogenic gastric inflammation and SPEM. Treatment of female mice with DHT prevented gastric inflammation and SPEM development when administered concurrent with adrenalectomy and also reversed the pathology when administered after disease onset. Single-cell RNAseq of gastric leukocytes revealed that ILC2s expressed abundant levels of both the glucocorticoid receptor (Gr) and androgen receptor (Ar). We demonstrated that DHT treatment potently suppressed the expression of the proinflammatory cytokines Il13 and Csf2 by ILC2s. Moreover, ILC2 depletion protected the stomach from SPEM development.<br />Conclusions: Here, we report a novel mechanism by which glucocorticoids and androgens exert overlapping effects to regulate gastric inflammation. Androgen signaling within ILC2s prevents their pathogenic activation by suppressing the transcription of proinflammatory cytokines. This work revealed a critical role for sex hormones in regulating gastric inflammation and metaplasia.<br /> (Published by Elsevier Inc.)
- Subjects :
- Adrenalectomy
Animals
Cellular Microenvironment
Disease Models, Animal
Disease Susceptibility
Female
Gastric Mucosa immunology
Gastric Mucosa metabolism
Gastric Mucosa pathology
Gastritis, Atrophic immunology
Gastritis, Atrophic pathology
Gastritis, Atrophic prevention & control
Granulocyte-Macrophage Colony-Stimulating Factor genetics
Granulocyte-Macrophage Colony-Stimulating Factor metabolism
Homeodomain Proteins genetics
Homeodomain Proteins metabolism
Intercellular Signaling Peptides and Proteins metabolism
Interleukin-13 genetics
Interleukin-13 metabolism
Interleukin-33 genetics
Interleukin-33 metabolism
Lymphocytes immunology
Lymphocytes metabolism
Male
Metaplasia
Mice, Inbred C57BL
Orchiectomy
Receptors, Androgen genetics
Receptors, Androgen metabolism
Receptors, Glucocorticoid genetics
Receptors, Glucocorticoid metabolism
Sex Factors
Signal Transduction
Thy-1 Antigens genetics
Thy-1 Antigens metabolism
Mice
Androgens pharmacology
Anti-Inflammatory Agents pharmacology
Dihydrotestosterone pharmacology
Gastric Mucosa drug effects
Gastritis, Atrophic metabolism
Glucocorticoids metabolism
Gonadal Steroid Hormones metabolism
Lymphocytes drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0012
- Volume :
- 161
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Gastroenterology
- Publication Type :
- Academic Journal
- Accession number :
- 33971182
- Full Text :
- https://doi.org/10.1053/j.gastro.2021.04.075