INTRODUCTION: Circulating DNA can be pro-inflammatory when detected by leukocytes via toll-like receptor 9 (TLR9). Cell-free fetal DNA (cff-DNA) of placental origin, circulates in pregnancy, and increased concentrations are seen in conditions associated with placental and maternal inflammation such as pre-eclampsia. However, whether cff-DNA is directly pro-inflammatory in pregnant women and what regulates cff-DNA levels in pregnancy are unknown.
METHODS: Using a human term placental explant model, we examined whether induction of placental inflammation can promote cff-DNA release, and the capacity of this cff-DNA to stimulate peripheral blood mononuclear cells (PBMCs) from pregnant women.
RESULTS: We demonstrate lipopolysaccharide (LPS)-mediated inflammation in placental explants and induced apoptosis after 24 h. However, this did not increase levels of cff-DNA generation compared to controls. Furthermore, the methylation status of the cff-DNA, was not altered by LPS-induced inflammation. Cff-DNA did not elicit production of inflammatory cytokines from PBMCs, in contrast to exposure to LPS or the TLR9 agonist CpG-ODN. Finally, we demonstrate that cff-DNA acquired directly from pregnant women did not differ in methylation status from placental extracted DNA, or from placental explant generated cell-free DNA, and that, unlike Escherichia coli DNA, this cff-DNA has a low level of unmethylated CpG sequences.
DISCUSSION: Our data suggest that placental inflammation does not increase release of cff-DNA and that placental cff-DNA is not pro-inflammatory to circulating PBMCs. It thus seems unlikely that high levels of cff-DNA are either a direct consequence or cause of inflammation observed in obstetric complications.
|Number of pages||7|
|Early online date||24 Feb 2020|
|Publication status||Published - 1 Apr 2020|
Bibliographical noteCopyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.
- Cell-free fetal DNA
- Placental inflammation
- Preterm birth
- DNA methylation
- Toll-like receptor 9