Jonathan T Busada1, Kylie N Peterson2, Stuti Khadka3, Xiaojiang Xu4, Robert H Oakley2, Donald N Cook5, John A Cidlowski6. 1. Molecular Endocrinology Group, Signal Transduction Laboratory, North Carolina; Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine, Morgantown, West Virginia. Electronic address: jonathan.busada@hsc.wvu.edu. 2. Molecular Endocrinology Group, Signal Transduction Laboratory, North Carolina. 3. Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine, Morgantown, West Virginia. 4. Integrative Bioinformatics Support Group, Epigenetics and Stem Cell Biology Laboratory, North Carolina. 5. Immunogenetics Group, Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina. 6. Molecular Endocrinology Group, Signal Transduction Laboratory, North Carolina. Electronic address: cidlows1@niehs.nih.gov.
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. 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. Published by Elsevier Inc.
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. Published by Elsevier Inc.
Authors: Jacqueline-Yvonne Cephus; Matthew T Stier; Hubaida Fuseini; Jeffrey A Yung; Shinji Toki; Melissa H Bloodworth; Weisong Zhou; Kasia Goleniewska; Jian Zhang; Sarah L Garon; Robert G Hamilton; Vasiliy V Poloshukin; Kelli L Boyd; R Stokes Peebles; Dawn C Newcomb Journal: Cell Rep Date: 2017-11-28 Impact factor: 9.423
Authors: Alexander Sheh; Chung Wei Lee; Kenichi Masumura; Barry H Rickman; Takehiko Nohmi; Gerald N Wogan; James G Fox; David B Schauer Journal: Proc Natl Acad Sci U S A Date: 2010-08-10 Impact factor: 11.205
Authors: Anuya Paranjape; Oksana Chernushevich; Amina Abdul Qayum; Andrew J Spence; Marcela T Taruselli; Daniel Abebayehu; Brian O Barnstein; Jamie Josephine Avila McLeod; Bianca Baker; Gurjas S Bajaj; Alena P Chumanevich; Carole A Oskeritzian; John J Ryan Journal: J Leukoc Biol Date: 2016-07-21 Impact factor: 4.962
Authors: Masahiro Ohtani; Alexis García; Arlin B Rogers; Zhongming Ge; Nancy S Taylor; Shilu Xu; Koichiro Watanabe; Robert P Marini; Mark T Whary; Timothy C Wang; James G Fox Journal: Carcinogenesis Date: 2007-08-27 Impact factor: 4.944
Authors: Anne R Meyer; Amy C Engevik; Toni Madorsky; Erika Belmont; Matthew T Stier; Allison E Norlander; Mark A Pilkinton; Wyatt J McDonnell; Jared A Weis; Bogun Jang; Simon A Mallal; R Stokes Peebles; James R Goldenring Journal: Gastroenterology Date: 2020-09-04 Impact factor: 22.682
Authors: Paul L Shaffer; Arif Jivan; D Eric Dollins; Frank Claessens; Daniel T Gewirth Journal: Proc Natl Acad Sci U S A Date: 2004-03-22 Impact factor: 11.205