Thromb Haemost 2021; 121(07): 877-890
DOI: 10.1055/s-0040-1722225
Coagulation and Fibrinolysis

NETosis Markers in Pregnancy: Effects Differ According to Histone Subtypes

1  Department of Haematology, University Hospital, Nîmes, France
2  Research Laboratory EA 2992, Montpellier University, Montpellier, France
3  Faculty of Pharmaceutical and Biological Sciences, Montpellier University, Montpellier, France
,
Mathieu Fortier*
1  Department of Haematology, University Hospital, Nîmes, France
,
Laura Vincent
1  Department of Haematology, University Hospital, Nîmes, France
,
Christophe Demattei
4  Department of Biostatistics, Public Health and Innovation in Methodology, Nîmes University Hospital, Nîmes, France
,
Eve Mousty
5  Department of Gynecology and Obstetrics, University Hospital, Nîmes, France
,
Marielle Herzog
6  Belgian Volition SPRL, Parc Scientifique Crealys, Isnes, Belgium
,
Guillaume Rommelaere
6  Belgian Volition SPRL, Parc Scientifique Crealys, Isnes, Belgium
,
Eva Nouvellon
1  Department of Haematology, University Hospital, Nîmes, France
2  Research Laboratory EA 2992, Montpellier University, Montpellier, France
,
Eric Mercier
1  Department of Haematology, University Hospital, Nîmes, France
2  Research Laboratory EA 2992, Montpellier University, Montpellier, France
3  Faculty of Pharmaceutical and Biological Sciences, Montpellier University, Montpellier, France
,
Vincent Letouzey
5  Department of Gynecology and Obstetrics, University Hospital, Nîmes, France
7  Department of Artificial Polymers, Max Mousseron Institute of Biomolecules, Montpellier University, Montpellier, France
,
1  Department of Haematology, University Hospital, Nîmes, France
2  Research Laboratory EA 2992, Montpellier University, Montpellier, France
3  Faculty of Pharmaceutical and Biological Sciences, Montpellier University, Montpellier, France
8  Department of Gynecology, I. M. Sechenov First Moscow State Medical University, Moscow, Russian Federation
› Author Affiliations

Abstract

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.

Authors' Contributions

S.B. designed the research, analyzed the data, and wrote the manuscript. M.F. performed the research, analyzed the data, and wrote the manuscript. L.V. performed the research. C.D. analyzed the data. E.Mo. and V.L. included participants in the main study. M.H and G.R. performed the ELISA tests. E.N. and E.Me analyzed the data. J.-C.G. designed the research and analyzed the data.


* These authors contributed equally in this work.


Supplementary Material



Publication History

Received: 30 June 2020

Accepted: 18 November 2020

Publication Date:
10 January 2021 (online)

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