Increased Neutrophil Activation and Plasma DNA Levels in Patients with Pre-Eclampsia

Hu, Yae; Li, Hui; Yan, Rui; Wang, Can; Wang, Yun; Zhang, Ce; Li, Meng; Zhou, Tiantian; Zhu, Weipei; Zhang, Hong; Dong, Ningzheng; Wu, Qingyu

doi:10.1055/s-0038-1675788

Cited by 29 publications

(34 citation statements)

References 56 publications

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“…This latest observation is in agreement with the Hu et al's study showing that total plasma histones and H3 alone are increased in PE. 6 But, contrary to their results, we observed a significant change for the pregnant population compared with the nonpregnant group while they did not. This discrepancy can be explained by the fact that we analyzed samples at term of pregnancy when theirs are from around 20 weeks.…”

Section: Discussioncontrasting

confidence: 99%

“…Several studies, including our data, 4 have shown that plasma nucleosomes and cell-free DNA (cfDNA) increased during pregnancy, and that their levels were even higher in women with PMPCs, particularly in PE. 5,6 Nucleosomes are key components of neutrophil extracellular traps (NETs) and are released by neutrophil activation, a process called NETosis. 7 Aberrant NETosis has been described in PE patients.…”

Section: Introductionmentioning

confidence: 99%

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NETosis Markers in Pregnancy: Effects Differ According to Histone Subtypes

et al. 2021

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NETosis is an innate immune response occurring after infection or inflammation: activated neutrophils expel decondensed DNA in complex with histones into the extracellular environment in a controlled manner. It activates coagulation and fuels the risk of thrombosis. Human pregnancy is associated with a mild proinflammatory state characterized by circulatory neutrophil activation which is further increased in complicated pregnancies, placenta-mediated complications being associated with an increased thrombotic risk. This aberrant activation leads to an increased release of nucleosomes in the blood flow. The aim of our study was to initially quantify nucleosome-bound histones in normal pregnancy and in placenta-mediated complication counterpart. We analyzed the role of histones on extravillous trophoblast function. Circulating nucleosome-bound histones H3 (Nu.QH3.1, Nu.QH3PanCit, Nu.QH3K27me3) and H4 (Nu.QH4K16Ac) were increased in complicated pregnancies. In vitro using the extravillous cell line HTR-8/SVNeo, we observed that free recombinant H2B, H3, and H4 inhibited migration in wound healing assay, but only H3 also blocked invasion in Matrigel-coated Transwell experiments. H3 and H4 also induced apoptosis, whereas H2B did not. Finally, the negative effects of H3 on invasion and apoptosis could be restored with enoxaparin, a low-molecular-weight heparin (LMWH), but not with aspirin. Different circulating nucleosome-bound histones are increased in complicated pregnancy and this would affect migration, invasion, and induce apoptosis of extravillous trophoblasts. Histones might be part of the link between the risk of thrombosis and pregnancy complications, with an effect of LMWH on both.

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Section: Discussioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 99%

NETosis Markers in Pregnancy: Effects Differ According to Histone Subtypes

et al. 2021

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“…29,30 In a prospective study, Hu et al showed that cell-free DNA and nucleosomes were elevated in preeclampsia. 31 Our study is the first to investigate different subtypes of severe placenta-mediated complications in a prospective design, with data from non-pregnant women and from normal pregnancies.…”

Section: Discussionmentioning

confidence: 99%

Placenta‐mediated complications: Nucleosomes and free DNA concentrations differ depending on subtypes

Bouvier

Mousty

Fortier

et al. 2020

Journal of Thrombosis and Haemostasis

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Background: Placenta-mediated pregnancy complications generate short-and longterm adverse medical outcomes for both the mother and the fetus. Nucleosomes and free DNA (fDNA) have been described in patients suffering from a wide range of inflammatory conditions. Objective: The objective of our study was to compare nucleosomes and fDNA circulating levels during pregnancy and particularly in women developing a placenta-mediated complication according to the subtype (preeclampsia or intrauterine growth restriction) (NCT 01736826). Patients/Methods: A total of 115 women were prospectively included in the study across three groups: 30 healthy non-pregnant women, 50 with normal pregnancy, and 35 with a complicated pregnancy. Blood samples were taken up to every 4 weeks for several women with normal pregnancy and nucleosomes and fDNA were quantified using enzyme-linked immunosorbent assay and quantitative polymerase chain reaction, respectively. Results: We show that nucleosomes and fDNA concentrations significantly increase during normal pregnancy, with concentrations at delivery differing between the two groups. Interestingly, we show that concentrations differ according to the type of placenta-mediated complications, with higher levels in preeclampsia compared to intrauterine growth restriction. Conclusions: These data suggest that nucleosomes and fDNA may be additional actors participating in placenta-mediated pregnancy complications.

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“…Isolated NETs were stored at −80°C until further use as previously reported ( 28 ). To investigate the effect of the TME on NETs formation, neutrophils were treated using 20% plasma from the same patients with GC (n=20) or the controls (n=10) as above, following a previously described protocol ( 29 ).…”

Section: Methodsmentioning

confidence: 99%

Neutrophil extracellular traps promote gastric cancer metastasis by inducing epithelial‑mesenchymal transition

Zhu

Zou

Yang³

et al. 2021

Int J Mol Med

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The risks of tumor recurrence following the successful resection of the primary tumor have been known for decades; however, the precise mechanisms underlying treatment failures remain unknown. The formation of neutrophil extracellular traps (NETs) has increasingly been demonstrated to be associated with thrombi formation in cancer patients, as well as with the development and metastasis of cancer. The present study demonstrated that the level of peripheral blood NETs in patients with gastric cancer (Gc) was associated with tumor progression, and patients with stage III/IV disease exhibited significant differences compared with the healthy controls and patients with stage I/II disease, which may be associated with an increased risk of metastasis. In addition, plasma from patients with stage III/IV Gc was more prone to stimulate neutrophils to form NETs; thus, it was hypothesized that the formation of NETs may be affected by the tumor microenvironment. A higher deposition of NETs in Gc tissues compared with normal resection margins was also identified. In vitro, following treatment with phorbol myristate acetate, which promotes the formation of NETs, or with dNAse-1/GSK-484, which inhibits the formation of NETs, it was found that the tumor migratory ability was altered; however, no significant changes were observed in cell proliferation and cell cycle progression. Epithelial-mesenchymal transition (EMT) is a key event associated with dissemination and metastasis in Gc pathogenesis. Finally, the present study demonstrated that NETs promote a more aggressive mesenchymal phenotype and promote the progression of Gc in vitro and in vivo. On the whole, to the best of our knowledge, the present study reports a previously unknown role of NETs in the regulation of Gc, which is associated with EMT and migration. Therefore, targeting NETs may prove to be therapeutically beneficial.

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Increased Neutrophil Activation and Plasma DNA Levels in Patients with Pre-Eclampsia

Cited by 29 publications

References 56 publications

NETosis Markers in Pregnancy: Effects Differ According to Histone Subtypes

NETosis Markers in Pregnancy: Effects Differ According to Histone Subtypes

Placenta‐mediated complications: Nucleosomes and free DNA concentrations differ depending on subtypes

Neutrophil extracellular traps promote gastric cancer metastasis by inducing epithelial‑mesenchymal transition

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