Proteases Activate Pregnancy Neutrophils by a Protease-Activated Receptor 1 Pathway: Epigenetic Implications for Preecla
- PDF / 2,736,074 Bytes
- 13 Pages / 595.276 x 790.866 pts Page_size
- 22 Downloads / 136 Views
PREECLAMPSIA: ORIGINAL ARTICLE
Proteases Activate Pregnancy Neutrophils by a Protease-Activated Receptor 1 Pathway: Epigenetic Implications for Preeclampsia Scott W. Walsh 1,2 & William H. Nugent 1 & Marwah Al Dulaimi 1 & Sonya L. Washington 1 & Phoebe Dacha 1 & Jerome F. Strauss III 1 Received: 28 February 2020 / Revised: 4 May 2020 / Accepted: 3 June 2020 # Society for Reproductive Investigation 2020
Abstract We tested a novel hypothesis that elevated levels of proteases in the maternal circulation of preeclamptic women activate neutrophils due to their pregnancy-specific expression of protease-activated receptor 1 (PAR-1). Plasma was collected longitudinally from normal pregnant and preeclamptic women and analyzed for MMP-1 and neutrophil elastase. Neutrophils were isolated for culture and confocal microscopy. Omental fat was collected for immunohistochemistry. Circulating proteases were significantly elevated in preeclampsia. Confocal microscopy revealed that tet methylcytosine dioxygenase 2 (TET2), a DNA demethylase, and p65 subunit of NF-κB were strongly localized to the nucleus of untreated neutrophils of preeclamptic women, but in untreated neutrophils of normal pregnant women they were restricted to the cytosol. Treatment of normal pregnancy neutrophils with proteases activated PAR-1, leading to activation of RhoA kinase (ROCK), which triggered translocation of TET2 and p65 from the cytosol into the nucleus, mimicking the nuclear localization in neutrophils of preeclamptic women. IL-8, an NF-κBregulated gene, increased in association with TET2 and p65 nuclear localization. Co-treatment with inhibitors of PAR-1 or ROCK prevented nuclear translocation and IL-8 did not increase. Treatment of preeclamptic pregnancy neutrophils with inhibitors emptied the nucleus of TET2 and p65, mimicking the cytosolic localization of normal pregnancy neutrophils. Expression of PAR-1 and TET2 were markedly increased in omental fat vessels and neutrophils of preeclamptic women. We conclude that elevated levels of circulating proteases in preeclamptic women activate neutrophils due to their pregnancy-specific expression of PAR-1 and speculate that TET2 DNA de-methylation plays a role in the inflammatory response. Keywords Preeclampsia . Neutrophils . Matrix metalloprotease 1 . Neutrophil elastase . Protease-activated receptor 1 . RhoA kinase . Tet methylcytosine dioxygenase 2 . NF-κB . Interleukin-8
Introduction Preeclampsia is a hypertensive disorder of pregnancy that affects multiple maternal organs, placental function, and fetal well-being. It occurs in 5–7% of all pregnancies, and is a leading cause of maternal and fetal morbidity and mortality [1]. Although the cause of preeclampsia is not known, the
* Scott W. Walsh [email protected] 1
Department of Obstetrics and Gynecology, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298-0034, USA
2
Department of Physiology and Biophysics, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298-0034, USA
pregnancy-specific express
Data Loading...
