title: Multimodal Regulation of NET Formation in Pregnancy: Progesterone Antagonizes the Pro-NETotic Effect of Estrogen and G-CSF.
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.
authors.affiliation: Department of Biomedicine, University Hospital Basel, Basel, Switzerland; Department of Rheumatology, Cantonal Hospital Aarau, Aarau, Switzerland.
authors.forename: Stavros
authors.initials: S
authors.lastname: Giaglis
authors.affiliation: Department of Biomedicine, University Hospital Basel , Basel , Switzerland.
authors.forename: Maria
authors.initials: M
authors.lastname: Stoikou
authors.affiliation: Department of Biomedicine, University Hospital Basel , Basel , Switzerland.
authors.forename: Chanchal
authors.initials: C
authors.lastname: Sur Chowdhury
authors.affiliation: Department of Biomedicine, University Hospital Basel , Basel , Switzerland.
authors.forename: Guenther
authors.initials: G
authors.lastname: Schaefer
authors.affiliation: Department of Biomedicine, University Hospital Basel, Basel, Switzerland; Department Clinical Sciences, Polytechnic University Marche, Ancona, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Grimolizzi
authors.affiliation: Department of Biomedicine, University Hospital Basel , Basel , Switzerland.
authors.forename: Simona W
authors.initials: SW
authors.lastname: Rossi
authors.affiliation: University Women's Hospital, University Hospital Basel , Basel , Switzerland.
authors.forename: Irene Mathilde
authors.initials: IM
authors.lastname: Hoesli
authors.affiliation: University Women's Hospital, University Hospital Basel , Basel , Switzerland.
authors.forename: Olav
authors.initials: O
authors.lastname: Lapaire
authors.affiliation: Department of Rheumatology, Cantonal Hospital Aarau , Aarau , Switzerland.
authors.forename: Paul
authors.initials: P
authors.lastname: Hasler
authors.affiliation: Department of Biomedicine, University Hospital Basel , Basel , Switzerland.
authors.forename: Sinuhe
authors.initials: S
authors.lastname: Hahn
keywords: G-CSF; NETs; neutrophils; pregnancy; sex hormones