Related Experiment Video
Updated: Jan 5, 2026
Using Nicotine in a Silica-Exposed Mouse Model to Promote Lung Epithelial-Mesenchymal Transition
Published on: March 3, 2023
Attenuated cholesterol metabolism pathway suppresses regulatory T cell development in prenatal nicotine exposed
Xiao Wen1, Wen-Hao Zhao1, Lan-Zhou Chen2
1Department of Pharmacology, Wuhan University School of Basic Medical Sciences, Wuhan 430071, China.
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.
Insights
Prenatal nicotine exposure (PNE) impairs regulatory T cell (Treg) development by disrupting cholesterol homeostasis, leading to immune dysfunction. Restoring cholesterol levels can reverse these effects, suggesting a key mechanism for PNE-induced immune suppression.
Area of Science:
- Immunology
- Developmental Biology
- Molecular Biology
Background:
- Regulatory T cells (Tregs) are crucial for immune tolerance and preventing autoimmune disease.
- Prenatal nicotine exposure (PNE) has been linked to reduced Treg frequency in offspring, but underlying mechanisms remain unclear.
- Cellular cholesterol homeostasis plays a role in immune cell function.
Purpose of the Study:
- To investigate the molecular mechanisms by which PNE inhibits Treg development.
- To explore the role of cellular cholesterol homeostasis in PNE-induced Treg suppression.
- To examine the impact of PNE on the mTOR and STAT5/Foxp3 pathways in Tregs.
Main Methods:
- Established a PNE mouse model using nicotine administration during gestation.
- Analyzed thymic Treg frequency, mTOR activation, and p-STAT5/Foxp3 pathway in offspring.
- Utilized in vitro nicotine treatment of primary thymocytes and cholesterol-replenishment experiments.
- Employed Abcg1 siRNA transfection to assess the role of ABCG1.
Main Results:
- PNE significantly decreased thymic Treg frequency in neonatal offspring.
- PNE led to mTOR activation and downregulation of the p-STAT5/Foxp3 pathway in Tregs.
- PNE elevated ATP-binding cassette transporter G1 (ABCG1) expression, reducing intracellular cholesterol in Tregs.
- Cholesterol replenishment and Abcg1 siRNA partially reversed PNE-induced Treg suppression.
Conclusions:
- PNE suppresses Treg development in female mice by up-regulating ABCG1-dependent cholesterol efflux.
- Impaired intracellular cholesterol homeostasis in Tregs is a key mechanism of PNE-induced immune suppression.
- Early-life PNE-induced Treg recession may be a developmental origin of later-life immune dysfunction.
