Abstract
Changes in decidual macrophage polarization affect local inflammatory microenvironment and lead to adverse pregnancy outcomes. However, the regulatory mechanism of macrophage polarization in preeclampsia (PE) remains unclear. In this study, we found that α7nAChR expression was significantly down-regulated in decidual macrophages in PE patients compared to normal pregnant women, accompanied by a reduced proportion of M2 phenotype and an increased proportion of M1 phenotype; these results suggested that the reduced α7nAChR activity might contribute to changes in the polarization of decidual macrophages. Then, we further investigated the regulatory role of α7nAChR activation by nicotine on decidual macrophage polarization and placental remodeling in the PE-like mouse model. The PE mice were obtained by i.p. injection of 10 µg/kg lipopolysaccharide (LPS) gestational day (GD) 13, and 40 µg/kg LPS daily until GD16. Subcutaneous injection of 1.0 mg/kg nicotine was administrated from GD14 to GD18. Nicotine treatment increased the decreased M2 phenotype and inhibited the increased M1 phenotype in decidua of pregnant mice induced by LPS. The levels of pro-inflammatory cytokines in decidua were higher but the levels of anti-inflammatory cytokines were lower in PE mice compared to the controls, nicotine reversed these changes. The level of choline acetyltransferase (CHAT) was reduced in the LPS-treated group, it was increased following nicotine treatment. Damage of spiral artery remodeling and down-regulation of markers related to trophoblast invasion in placentas were found in PE mice; nicotine improved these pathological structures of placentas. α-bungarotoxin (α-BGT) which is specific antagonist for α7nAChR could abolish the effects of nicotine on decidual macrophage polarization, trophoblast arrangement and vascular structure in placental tissue in PE mice. These results suggest that α7nAChR plays an important regulatory role in maternal-fetal inflammation and placental remodeling in preeclampsia and may provide a theoretical basis for the discovery of new strategies for preeclampsia.
Highlights
Preeclampsia (PE) is a specific disorder of pregnancy that is characterized by hypertension, proteinuria and other symptoms including headache, vomiting, kidney and liver dysfunction [1, 2]
The a7nAChR antagonist reversed the effects of nicotine
Quantitative analysis showed a similar changing tendency in all groups to that observed from the HE staining images. These data suggest that activating a7nAChR-mediated cholinergic antiinflammatory pathway can reduce LPS-induced placental injury in pregnant mice
Summary
Preeclampsia (PE) is a specific disorder of pregnancy that is characterized by hypertension, proteinuria and other symptoms including headache, vomiting, kidney and liver dysfunction [1, 2]. In PE patients, the number of circulating leukocytes, neutrophils, and serum levels of tumor necrosis factor-a (TNF-a), interleukin-6 (IL-6), C-reactive protein (CRP) were significantly increased compared to normal pregnancy [4]. LPS could increase the secretion of IL-6 and IL-8 from extravillous trophoblast (EVT) but decrease the invasion of EVT [7]. Elevated concentrations of TNF-a directly impaired trophoblast invasion in first-trimester villous explant cultures [8]. These findings suggest that excessive inflammatory state at maternalfetal interface inhibits trophoblast invasion and contributes to the development of PE. The specific mechanisms mediating this process are still under investigation
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