Placental Chemokine Receptor D6 Is Functionally Impaired in Pre-Eclampsia

Abstract

BackgroundPre-eclampsia (PE) is a major cause of maternal and perinatal morbidity and mortality worldwide. It is defined by new onset of hypertension and proteinuria after the 20th week of gestation and characterized by systemic exaggerated inflammatory response. D6 is a chemokines scavenger receptor that binds with high affinity CC chemokines, internalizes and targets the ligands for degradation. It is expressed in trophoblast-derived tissues and prevents excessive placenta leukocyte infiltration.The aim of this study was to investigate the expression and function of D6 in human placentae from pre-eclamptic and healthy pregnant women.Methods and ResultsPlasma levels of D6-binding CC chemokines (CCL-2, CCL-3, CCL-4, CCL-7, CCL-11) and pro-inflammatory cytokines (IL-6, TNF-α, CRP) were analyzed in 37 healthy pregnant women and 38 patients with PE by multiplex bead assay. Higher circulating levels of CCL7, CCL11, IL-6, (p<0.0001) and CRP (p<0.05) were observed in PE women compared to controls. Levels of circulating CCL4 were decreased in PE (p<0.001), while no significant differences of CCL2, CCL3 or TNF-α levels were detected. Immunofluorescent staining of placental sections showed higher expression of D6 receptor in the PE syncytiotrophoblast. Confocal and Western blot (WB) analyses revealed a prevalent distribution of D6 in trophoblast cells membranes in PE. Increased activation of D6 intracellular pathway was observed by Western blot analyses of p-LIMK and p-cofilin in trophoblast cell lysates. D6 functional assays showed reduced scavenging of CCL2 in PE cells compared to controls. Since actin filaments spatial assembling is essential for D6 intracellular trafficking and scavenging activity, we investigated by confocal microscopy trophoblast cytoskeleton organization and we observed a dramatic disarrangement in PE compared to controls.Conclusionsour results suggest membrane distribution of D6 receptor on trophoblast cell membranes in PE, together with reduced functionality, probably due to cytoskeleton impairment.

Specific inflammatory profile in each pregnancy complication: A comparative study

“…MIP‐1α and MIP‐1β are two chemokines attracting polymorphonuclear leucocytes or NK cell and monocytes, respectively 32 . Decreased MIP‐1β has been previously observed in the maternal circulation of PE women as compared to healthy pregnancy 33 similarly to what we observed. In contrast to what we found, IL‐18 has been shown to be elevated in the maternal serum at delivery and particularly in pregnancies complicated by IUGR and PTB 34 .…”

Abnormal uterine inflammation in obstetric syndromes: molecular insights into the role of chemokine decoy receptor D6 and inflammasome NLRP3

“…It is required for actin depolymerization and cytoskeleton rearrangement, which is essential for chemokines degradation by D6 receptor and its recycling from intracellular pool to cell membrane. The observation of an increased phosphorylation of LIMK1 and cofilin in trophoblast cells from PE is coherent with the increased relative abundance of D6-specific chemokines (like CCL-2, CCL-7 and CCL-11), which are expected to be in trophoblast extracellular environment in PE (Tersigni et al, 2016). Indeed, in PE circulating levels, chemokines are increased, thus trophoblast D6 receptor is expected to be saturated, which is consistent with the downstream intracellular signaling over-activation.…”

“…to cells from normal placentae. This may be secondary to significant cytoskeletal disarrangement, which was noted in PE trophoblast compared to controls (Tersigni et al, 2016). Decreased expression of placental D6 decoy receptor at both transcriptional and protein levels has also been reported in PE (Cho et al, 2015), although we could not confirm this observation in our studies (Tersigni et al, 2016).…”

“…Recently, we have investigated the expression and function of chemokines D6 decoy receptor in the placentae of women who developed PE. Higher circulating levels of both D6specific chemokines, like CCL-7 and CCL-11, and pro-inflammatory cytokines, like IL-6 and C reactive protein, were found in serum of pre-eclamptic compared to healthy pregnant women (Tersigni et al, 2016). It is of note that in cytotrophoblast cells isolated from normal placentae, D6 receptor was found to be mainly localized in intracellular compartments, consistent with previous reports (Madigan et al, 2010), while in PE, D6 showed a characteristic distribution on cytotrophoblast cell membranes.…”

“…This may be secondary to significant cytoskeletal disarrangement, which was noted in PE trophoblast compared to controls (Tersigni et al, 2016). Decreased expression of placental D6 decoy receptor at both transcriptional and protein levels has also been reported in PE (Cho et al, 2015), although we could not confirm this observation in our studies (Tersigni et al, 2016). Our hypothesis is that in PE, higher circulating and placental levels of pro-inflammatory chemokines might bind to syncytiotrophoblast membrane D6 decoy receptor, inducing an increased concentration of the scavenger on the syncytiotrophoblast cell membranes, due to its mobilization from the intracellular pool (Fig.…”