Multimodal regulation of NET formation in pregnancy: Progesterone antagonizes the pro-NETotic effect of estrogen and G-CSF

Stavros Giaglis, Maria Stoikou, Chanchal Sur Chowdhury, Guenther Schaefer, Franco Grimolizzi, Simona W. Rossi, Irene Mathilde Hoesli, Olav Lapaire, Paul Hasler, Sinuhe Hahn

Research output: Contribution to journalArticlepeer-review

72 Scopus citations

Abstract

Human pregnancy is associated with a mild pro-inflammatory state, characterized by circulatory neutrophil activation. In order to explore the mechanism underlying this alteration, we examined NETosis during normal gestation. Our data indicate that neutrophils exhibit a pro-NETotic state, modulated in a multimodal manner during pregnancy. In general, circulatory granulocyte colony-stimulating factor, the levels of which increase during gestation, promotes neutrophil extracellular trap (NET) formation. Early in pregnancy, NETosis is enhanced by chorionic gonadotropin,whereas toward term is stimulated by estrogen. A complex interaction between estrogen and progesterone arises, wherein progesterone restrains the NETotic process. In this state, extensive histone citrullination is evident, yet full NETosis is inhibited. This coincides with the inability of neutrophil elastase to translocate from the cytoplasm to the nucleus and is regulated by progesterone. Our findings provide new insight concerning gestational and hormone-driven pathologies, since neutrophil recruitment, activation, and NET release could be associated with excessive endothelial and placental injury.

Original languageEnglish
Article number565
JournalFrontiers in immunology
Volume7
Issue numberDEC
DOIs
StatePublished - 2016

Keywords

  • G-CSF
  • NETs
  • Neutrophils
  • Pregnancy
  • Sex hormones

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