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Attenuated cholesterol metabolism pathway suppresses regulatory T cell development in prenatal nicotine exposed female mice.

Authors
  • Wen, Xiao1
  • Zhao, Wen-Hao1
  • Chen, Lan-Zhou2
  • Qu, Wen1
  • Liu, Han-Xiao1
  • Yan, Hui-Yi1
  • Hou, Li-Fang1
  • Ping, Jie3
  • 1 Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, China. , (China)
  • 2 Hubei Key Laboratory of Biomass-Resources Chemistry and Environmental Biotechnology, Wuhan University School of Resource and Environmental Sciences, Wuhan, 430079, China. , (China)
  • 3 Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, China. Electronic address: [email protected] , (China)
Type
Published Article
Journal
Toxicology
Publication Date
Dec 01, 2019
Volume
428
Pages
152309–152309
Identifiers
DOI: 10.1016/j.tox.2019.152309
PMID: 31629012
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

The recession of regulatory T cells (Tregs) contributes to development of autoimmune disease. Our previous study suggested that prenatal nicotine exposure (PNE) inhibited Tregs frequency in offspring, but the mechanisms are still uncertain. This study aimed to explore the molecular mechanisms of PNE-induced Tregs inhibition from the perspective of cellular cholesterol homeostasis both in vivo and in vitro. PNE mice model were established by 3 mg/kg/d nicotine administration in Balb/c strain from gestational day (GD) 9 to GD 18. The results showed that PNE significantly decreased thymic Tregs frequency in neonatal offspring. The activation of mTOR and downregulation of p-STAT5/Foxp3 pathway of Tregs were observed in PNE offspring. Mechanism study found that PNE elevated ATP-binding cassette transporter G1 (ABCG1) expression and decreased intracellular cholesterol content of Tregs in offspring, indicating impaired intracellular cholesterol homeostasis. Similar results were observed in 1 μM nicotine-treated primary thymocytes in vitro. Further, cholesterol-replenishment can abrogate nicotine-induced mTOR activation and the following suppression of p-STAT5/Foxp3 pathway and Tregs frequency. In addition, Abcg1 siRNA transfection can partly reverse the nicotine-decreased intracellular cholesterol content and cell frequency of Tregs. In conclusion, this study showed that PNE could suppress Tregs development in female mice by up-regulating ABCG1-dependent cholesterol efflux, and suggested that PNE-induced thymic Tregs recession of offspring at early life was the developmental origin mechanism of immune dysfunction in later life. Copyright © 2019 Elsevier B.V. All rights reserved.

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