NETosis Markers in Pregnancy: Effects Differ According to Histone Subtypes

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.

Assessment‐based management of placenta‐mediated pregnancy complications: Pragmatism until a precision medicine approach evolves

“…Stepping away from descriptive and deterministic studies will allow for a more precise assessment of the pathologic evolution during implantation and placentation, and so guide treatment that will specifically impact the disease mechanism active in the patient. In that sense, it would be plausible to investigate early markers of placental dysfunction 83 and study the effects of anticoagulants on placental development, 84 where a specific disease mechanism is targeted. Genome‐wide association studies (GWAS) in the setting of RPLs and PMCs are scarce, 85 but could be invaluable in examining the complex physiology of placentation and disease processes.…”

Advisory Board conclusion following the discussion "Controversial issues of low molecular weight heparins use in obstetrics"

“…В.О. Бицадзе, были посвящены влиянию терапии на циркулирующие, связанные с нуклеосомами гистоны Н3 (Н3.1, Н3PanCit, Н3К27me3) и Н4 (H4K16Ac), которые увеличиваются во время беременности и в большей степени при ПАО, что подчеркивает роль нетоза в развитии ПЭ [18]. Количество различных циркулирующих, связанных с нуклеосомами гистонов Н3 и Н4 при осложненной беременности увеличивается, и это влияет на миграцию, инвазию и индукцию апоптоза вне ворсинчатого трофобласта.…”

“…Собственно поэтому гистоны могут быть связующим звеном между риском тромбоза и осложнениями беременности, а НМГ могут влиять на нормализацию этих процессов. Выявлено, что негативное влияние H3 гистона на инвазию трофобласта и апоптоз может быть восстановлено с помощью НМГ, но не с помощью АСК [18]. При этом терапевтические эффекты НМГ при использовании на ранних этапах беременности весьма многогранны: прямое влияние на коагуляционный каскад, конкурентное ингибирование связывания β 2 -гликопротеина 1 (англ.…”