Glucocorticoids and Androgens Protect From Gastric Metaplasia by Suppressing Group 2 Innate Lymphoid Cell Activation.
Adrenalectomy
Androgens
/ pharmacology
Animals
Anti-Inflammatory Agents
/ pharmacology
Cellular Microenvironment
Dihydrotestosterone
/ pharmacology
Disease Models, Animal
Disease Susceptibility
Female
Gastric Mucosa
/ drug effects
Gastritis, Atrophic
/ immunology
Glucocorticoids
/ metabolism
Gonadal Steroid Hormones
/ metabolism
Granulocyte-Macrophage Colony-Stimulating Factor
/ genetics
Homeodomain Proteins
/ genetics
Intercellular Signaling Peptides and Proteins
/ metabolism
Interleukin-13
/ genetics
Interleukin-33
/ genetics
Lymphocytes
/ drug effects
Male
Metaplasia
Mice, Inbred C57BL
Orchiectomy
Receptors, Androgen
/ genetics
Receptors, Glucocorticoid
/ genetics
Sex Factors
Signal Transduction
Thy-1 Antigens
/ genetics
Gastric
ILC2
Macrophage
SPEM
Stomach
Journal
Gastroenterology
ISSN: 1528-0012
Titre abrégé: Gastroenterology
Pays: United States
ID NLM: 0374630
Informations de publication
Date de publication:
08 2021
08 2021
Historique:
received:
21
03
2020
revised:
13
04
2021
accepted:
27
04
2021
pubmed:
11
5
2021
medline:
19
1
2022
entrez:
10
5
2021
Statut:
ppublish
Résumé
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. 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. 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. 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.
Sections du résumé
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.
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.
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.
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.
Identifiants
pubmed: 33971182
pii: S0016-5085(21)00750-2
doi: 10.1053/j.gastro.2021.04.075
pmc: PMC8328958
mid: NIHMS1702440
pii:
doi:
Substances chimiques
AR protein, mouse
0
Androgens
0
Anti-Inflammatory Agents
0
Glucocorticoids
0
Gonadal Steroid Hormones
0
Homeodomain Proteins
0
Il33 protein, mouse
0
Intercellular Signaling Peptides and Proteins
0
Interleukin-13
0
Interleukin-33
0
Receptors, Androgen
0
Receptors, Glucocorticoid
0
Thy-1 Antigens
0
spasmolytic polypeptide
0
Dihydrotestosterone
08J2K08A3Y
RAG-1 protein
128559-51-3
Granulocyte-Macrophage Colony-Stimulating Factor
83869-56-1
Types de publication
Comparative Study
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
637-652.e4Subventions
Organisme : NIGMS NIH HHS
ID : FI2 GM123974
Pays : United States
Organisme : NIGMS NIH HHS
ID : P20 GM121322
Pays : United States
Organisme : NIGMS NIH HHS
ID : P20 GM103434
Pays : United States
Organisme : NIGMS NIH HHS
ID : P30 GM103488
Pays : United States
Organisme : NIGMS NIH HHS
ID : U54 GM104942
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA ES090057
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Published by Elsevier Inc.
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