Lipopolysaccharide-Stimulated Human Fetal Membranes Induce Neutrophil Activation and Release of Vital Neutrophil Extracellular Traps

Abstract

Preterm birth is a major contributor to neonatal mortality and morbidity, and infection is a major risk factor. Chorioamnionitis, inflammation of the placenta, and fetal membranes (FMs) are commonly observed in preterm birth and are characterized by neutrophil infiltration. However, interactions between FMs and neutrophils remain incompletely understood. The objectives of this study were to determine how FMs, with or without bacterial LPS stimulation, affect neutrophil recruitment, activation, and the formation of neutrophil extracellular traps (NETs) and to elucidate the signaling mechanisms involved. Using a combination of in vitro, ex vivo, and in vivo approaches, we show that human resting FMs can directly recruit neutrophils and induce them to produce proinflammatory factors. Furthermore, neutrophils release vital NETs in response to FM-derived factors. LPS-stimulated FMs further augmented neutrophil recruitment, inflammatory cytokine/chemokine secretion, and vital NET release and also induced reactive oxygen species production and degranulation. We demonstrate a role for FM-derived TNF-a in mediating these effects through activation of neutrophil p38 MAPK. We propose that, during infection, neutrophil recruitment and activation may neutralize pathogens, vital NET formation, and prolonged neutrophil viability, and in combination with degranulation, reactive oxygen species production and inflammatory chemokine/cytokine production may contribute to tissue injury at the maternal/fetal interface.

TNF-Signaling Modulates Neutrophil-Mediated Immunity at the Feto-Maternal Interface During LPS-Induced Intrauterine Inflammation

“…Indeed, there were no changes in the frequency of T cell, NK cells, iNKT cells in the chorio-decidua after LPS in our model. Recently, Tong et al reported that induction of neutrophil activation and Neutrophil Extracellular Trap (NET) release is mediated at least in part by fetal membrane-derived TNFα (11). We observed that the inhibition of TNF-signaling decreased LPS-induced neutrophil counts by 80% in the choriodecidua and by 50% in the amniotic fluid.…”

“…Here, we show that amnion expression of neutrophil chemokines is also TNFdependent. IL1 inhibition has overlapping results compared to TNF inhibition in the same rhesus macaque model of LPS-induced IUI (10,11). However, a notable difference is inhibition of LPS-induced AF PGE 2 levels with IL1-blockade FIGURE 9 | Model for pathogenesis of intrauterine infection/inflammation.…”

“…The histologic correlate of IUI is chorioamnionitis, defined as neutrophilic infiltration of the placenta, fetal membranes, and the amniotic fluid (6,7). During IUI, neutrophils are the most abundant leukocyte, and are activated to secrete proinflammatory mediators (8)(9)(10)(11). In contrast, small numbers of neutrophils are present in the chorio-decidua during normal gestation (12,13).…”

Small GTPase ARF6 Is a Coincidence-Detection Code for RPH3A Polarization in Neutrophil Polarization

“…Human neutrophils were isolated as previously described (48). Briefly, peripheral blood was collected from healthy, nonpregnant women and used immediately.…”

Human Chorionic Gonadotropin modulates CXCL10 Expression through Histone Methylation in human decidua

“…2. PBMC were added to the upper chamber and then exposed to CM in the lower chamber obtained from: (1) DSCs treated with vehicle (control) or (2) DSCs treated with LPS (100 ng/mL) for 48 h. This concentration of LPS has no detrimental effect on DSCs [60][61][62][63] . As shown in Fig.…”