Systemic Inflammatory Priming in Normal Pregnancy and Preeclampsia: The Role of Circulating Syncytiotrophoblast Microparticles

Abstract

Systemic inflammatory responsiveness was studied in normal human pregnancy and its specific inflammatory disorder, pre-eclampsia. Compared with nonpregnancy, monocytes were primed to produce more TNF-α throughout normal pregnancy, more IL-12p70 in the first and second trimesters, and more IL-18 in the first trimester only. Intracellular cytokine measurements (TNF-α and IL12p70) showed little change by comparison. IFN-γ production was suppressed in all three trimesters. In pre-eclampsia, IL-18 secretion was increased. Secreted but not intracellular measures of TNF-α and IL-12p70 were also further enhanced compared with normal pregnancy. Inhibition of IFN-γ production was lost and involved both CD56+ NK and CD56− lymphocyte subsets. We determined whether circulating syncytiotrophoblast microparticles (STBM) could contribute to these inflammatory changes. Unbound STBM could be detected in normal pregnancy by the second trimester and increased significantly in the third. They were also bound in vivo to circulating monocytes. Women with pre-eclampsia had significantly more circulating free but not cell-bound STBMs. STBMs prepared by perfusion of normal placental lobules stimulated production of inflammatory cytokines (TNF-α, IL12p70, and IL-18 but not IFN-γ) when cultured with PBMCs from healthy nonpregnant women. Inflammatory priming of PBMCs during pregnancy is confirmed and is established by the first trimester. It is associated with early inhibition of IFN-γ production. The inflammatory response is enhanced in pre-eclampsia with loss of the IFN-γ suppression. Circulating STBMs bind to monocytes and stimulate the production of inflammatory cytokines. It is concluded that they are potential contributors to altered systemic inflammatory responsiveness in pregnancy and pre-eclampsia.

Placenta-derived extracellular vesicles: their cargo and possible functions

“…Significantly higher levels in uterine venous blood vs peripheral venous blood in PE (28.7 vs 10.0 ng mL À1 ) and in uterine vs peripheral venous blood NP (9.1 vs 2.3 ng mL À1 ) Germain et al 2007 Blood samples taken from NP at first (n ¼ 10), second (n ¼ 10) and third (n ¼ 14) trimester and at delivery from PE (n ¼ 14). EV: two-step centrifugation ELISA using NDOG2 antibody In NP pregnancy, unbound STBEV plasma levels significantly increase during second and third trimester as determined by protein concentration (mean range 10-30 ng mL À1 vs first trimester 5 ng mL À1 ).…”

“…We (Messerli et al 2010) and others (Germain et al 2007) have shown that STBEVs can activate peripheral blood monocytes, inducing the release of various inflammatory cytokines, which has led to the suggestion that the higher levels of STBEVs may contribute to the systemic inflammatory response seen in PE (Redman et al 2012). In addition, several groups have shown, using in vitro models, that STBEVs can reduce proliferation and damage the integrity of cultured endothelial cell monolayers (Redman and Sargent 2009;Roberts and Escudero 2012).…”

Elevated venous thromboembolism risk in preeclampsia: molecular mechanisms and clinical impact

“…The preeclamptic placenta is hypoxic and experiences oxidative stress. It is postulated that the observed increased expression in preeclamptic patients of these circulating microparticles is a consequence of inflammatory and oxidative stress [9]. In an apparent 'positive feedback loop', STBM are capable of stimulating pro-inflammatory cytokine release when cultured in vitro with peripheral blood mononuclear cells [9].…”

“…It is postulated that the observed increased expression in preeclamptic patients of these circulating microparticles is a consequence of inflammatory and oxidative stress [9]. In an apparent 'positive feedback loop', STBM are capable of stimulating pro-inflammatory cytokine release when cultured in vitro with peripheral blood mononuclear cells [9]. Furthermore, STBMs collected by perfusion of the maternal side of placentae (taken at the time of caesarean section) from healthy pregnant women and women with preeclampsia have been shown to have TF activity in a calibrated automated thrombography assay, in which thrombin generation is determined by cleavage of a fluorogenic thrombin substrate [61].…”

“…Moreover, plasma levels of trophoblast (placenta)-derived, tissue factor (TF)-expressing microparticles are significantly elevated in patients with preeclampsia [9]. However, as we have recently described, the precise mechanisms underlying the preeclampsia-associated prothrombotic phenotype remain incompletely understood [10].…”