Abstract
Accumulation of activated neutrophils at the feto-maternal interface is a defining hallmark of intrauterine inflammation (IUI) that might trigger an excessive immune response during pregnancy. Mechanisms responsible of this massive neutrophil recruitment are poorly investigated. We have previously showed that intraamniotic injection of LPS in rhesus macaques induced a neutrophil predominant inflammatory response similar to that seen in human IUI. Here, we demonstrate that anti-TNF antibody (Adalimumab) inhibited ~80% of genes induced by LPS involved in inflammatory signaling and innate immunity in chorio-decidua neutrophils. Consistent with the gene expression data, TNF-blockade decreased LPS-induced neutrophil accumulation and activation at the feto-maternal interface. We also observed a reduction in IL-6 and other pro-inflammatory cytokines but not prostaglandins concentrations in the amniotic fluid. Moreover, TNF-blockade decreased mRNA expression of inflammatory cytokines in the chorio-decidua but not in the uterus, suggesting that inhibition of TNF-signaling decreased the inflammation in a tissue-specific manner within the uterine compartment. Taken together, our results demonstrate a predominant role for TNF-signaling in modulating the neutrophilic infiltration at the feto-maternal interface during IUI and suggest that blockade of TNF-signaling could be considered as a therapeutic approach for IUI, the major leading cause of preterm birth.
Highlights
About 25–40% of preterm births (PTB) are associated with intrauterine infection (IUI) [1] and other studies suggest that inflammation is implicated in as many as 90% of very early PTB [2]
To determine the gene expression profile of the infiltrating neutrophils after LPS-exposure, we analyzed comparative gene expression profiles of blood and chorio-decidua neutrophils in controls and experimental animals
We demonstrate that inhibition of Tumor necrosis factor (TNF)-signaling reduces LPS-induced inflammation in all the intrauterine subcompartments with the exception of the uterus
Summary
About 25–40% of preterm births (PTB) are associated with intrauterine infection (IUI) [1] and other studies suggest that inflammation is implicated in as many as 90% of very early PTB [2]. Apart from maternal morbidity, IUI causes fetal inflammation and increases the risk for fetal and newborn brain, gut, and lung injury in both clinical studies and in animal models [reviewed in [5]]. The histologic correlate of IUI is chorioamnionitis, defined as neutrophilic infiltration of the placenta, fetal membranes, and the amniotic fluid [6, 7]. The roles of neutrophils in the choriodecidua during normal pregnancy and IUI are not known. Neutrophil function at the maternal-fetal interface during normal pregnancy and in pathologic inflammatory conditions needs further investigation to improve our understanding of normal and preterm labor
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