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Updated: Jul 4, 2026
Isolation of Leukocytes from the Human Maternal-fetal Interface
Published on: May 21, 2015
α7 nicotinic acetylcholine receptor regulates decidual macrophage polarization through TLR4/NF-κB/HIF-1α-mediated
Hanbo Liu1, Yuguo Deng2, Lingyan Chen1
1Department of Obstetrics, Longgang District Maternity & Child Healthcare Hospital of Shenzhen City (Longgang Maternity and Child Institute of Shantou University Medical College), Shenzhen, Guangdong, China; Medical Research Institute of Maternal and Child, Longgang Maternity and Child Institute of Shantou University Medical College (Longgang District Maternity & Child Healthcare Hospital of Shenzhen City), Shenzhen, Guangdong, China.
Introduction:
Preeclampsia (PE) is a pregnancy-specific hypertensive disorder characterized by excessive inflammation at the maternal-fetal interface. The α7 nicotinic acetylcholine receptor (α7nAChR), a key mediator of the cholinergic anti-inflammatory pathway, is downregulated in decidual macrophages of PE patients, but the downstream mechanisms linking α7nAChR deficiency to macrophage inflammatory activation remain unclear. This study investigated whether α7nAChR deficiency promotes decidual macrophage M1 polarization through TLR4/NF-κB/HIF-1α-mediated glycolytic reprogramming.
Methods:
Decidual tissues from PE patients and gestational age-matched healthy controls were analyzed by immunofluorescence, Western blot, qRT-PCR, Seahorse metabolic analysis, and ELISA. siRNA-mediated α7nAChR knockdown in THP-1-derived macrophages followed by LPS/IFN-γ stimulation was used to establish causality. Pharmacological inhibitors targeting TLR4, NF-κB, HIF-1α, or glycolysis were employed for pathway validation. Trophoblast function was assessed using macrophage-trophoblast co-culture systems.
Results:
α7nAChR expression was significantly reduced in PE decidual macrophages and negatively correlated with TLR4, phosphorylated NF-κB, and HIF-1α levels. PE decidual macrophages exhibited enhanced M1 polarization, increased glycolytic enzyme expression, elevated extracellular acidification rate and pro-inflammatory cytokine secretion, with suppressed oxidative phosphorylation. In vitro, α7nAChR knockdown amplified LPS/IFN-γ-induced TLR4/NF-κB/HIF-1α signaling, glycolytic metabolism, and M1 polarization. These effects were attenuated by all four pathway inhibitors, confirming the hierarchical signaling cascade. Functionally, α7nAChR-deficient inflammatory macrophages induced trophoblast apoptosis and impaired invasion, both rescued by pathway inhibition.
Discussion:
α7nAChR deficiency amplifies inflammatory stimuli-induced decidual macrophage M1 polarization through TLR4/NF-κB/HIF-1α-dependent glycolytic reprogramming, linking cholinergic anti-inflammatory pathway dysfunction to immunometabolic dysregulation at the maternal-fetal interface in PE. Targeting macrophage metabolic reprogramming may represent a potential therapeutic strategy for PE.