NETosis in Pregnancy: Role of Different Histones Subtypes

M. Fortier¹, L. Vincent¹, E. Mousty², C. Demattei³, M. Herzog⁴, G. Rommelaere⁴, E. Mercier^1,5,6, E. Nouvellon¹, V. Letouzey^2,7, S. Bouvier^1,5,6, J.-C. Gris^1,5,6

¹Nîmes University Hospital, Department of Haematology, Nimes, France, ²Nîmes University Hospital, Department of Gynecology and Obstetrics, Nimes, France, ³Nîmes University Hospital, Department of Biostatistics, Public Health and Innovation in Methodology, Nimes, France, ⁴Belgian Volition SA, Isnes, Belgium, ⁵Montpellier University, Research Laboratory EA 2992, Montpellier, France, ⁶Faculty of Pharmaceutical and Biological Sciences, Montpellier University, Department of Haematology, Montpellier, France, ⁷Max Mousseron Institute of Biomolecules, CNRS UMR 5247, Montpellier University, Department of Artificial Polymers, Montpellier, France

Abstract Number: OC 11.5

Meeting: ISTH 2020 Congress

Theme: Women Health » Pregnancy and Pregnancy Complications

Background: NETosis is an innate immune response occurring after infection or inflammation. Dying neutrophils expel decondensed DNA, combined with histones into the extracellular environment in a controlled way. This activates coagulation and fuels the risk of thrombosis. Human pregnancy is associated with a mild pro-inflammatory state, characterized by circulatory neutrophil activation which is further increased in complicated pregnancies, placenta-mediated complications being associated with a high risk of thrombosis. This aberrant activation leads to an increased release of nucleosomes in the blood flow.

Aims: The initial aim of our study was to quantify histone-bound nucleosomes in normal pregnancies as opposed to those with placenta-mediated complicated. We then analyzed the role of histones on the function of extravillous trophoblasts.

Methods: Histones circulating in plasma from 50 normal and 35 complicated pregnancies (clinicaltrials.gov identifier: NCT04205383 and IRB CHU de Nîmes n°19.01.04) were quantified by ELISA. Trophoblast migration of the extravillous cell line HTR-8/SVNeo was analyzed by wound healing assay and their invasive potential by Matrigel-coated Transwell® experimentation. Apoptosis was characterized by flow cytometry.

Results: Circulating nucleosome-bound histones H3 and H4 were increased in complicated pregnancies. In vitro, we observed that free recombinant H2B, H3 and H4 inhibited collective migration, but only H3 also blocked invasion. 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.

Conclusions: Different circulating histones are increased in complicated pregnancy and this apparently affects migration, invasion and induces apoptosis of extravillous trophoblasts. Histones might be part of the link between the risk of thrombosis and pregnancy complications, and LMWH has an effect on both.

To cite this abstract in AMA style:

Fortier M, Vincent L, Mousty E, Demattei C, Herzog M, Rommelaere G, Mercier E, Nouvellon E, Letouzey V, Bouvier S, Gris J-. NETosis in Pregnancy: Role of Different Histones Subtypes [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/netosis-in-pregnancy-role-of-different-histones-subtypes/. Accessed October 1, 2023.

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