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

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.

Unique maternal immune and functional microbial profiles during prenatal stress

“…At the maternal-fetal interface, acute restraint stress on GD1 has been shown to disrupt endometrial lymphocyte concentrations and attenuate proliferation and cytokine secretion 68 . Shifts in intrauterine leukocyte populations, driven by localized cytokine signaling 69,70 , have been demonstrated in animal models of direct intrauterine inflammation 71 . However, the decrease in or absence of leukocyte recruitment in our study (in the placenta and uterus, respectively) indicates that prenatal stress is unique and distinct from these models.…”

Maternal regulation of inflammatory cues is required for induction of preterm birth

“…LPS challenge resulted in increased expression of type I interferons and interferon-stimulated genes ( Figure 1E), immune mediators associated with PTB (43). Similarly, genes encoding proinflammatory cytokines known to promote PTB (e.g., Il6, Tnf, and Il1b) (43)(44)(45)(46)(47)(48) were also upregulated at both 6 and 12 hours post-LPS challenge ( Figure 1F).…”

Unique maternal immune and functional microbial profiles during prenatal stress

“…At the maternal-fetal interface, acute restraint stress on GD1 has been shown to disrupt endometrial lymphocyte concentrations and attenuate proliferation and cytokine secretion 66 . Shifts in intrauterine leukocyte populations, driven by localized cytokine signaling 67,68 , have been demonstrated in animal models of direct intrauterine inflammation 69 . However, the decrease in or absence of leukocyte recruitment in our study (in the placenta and uterus, respectively) indicates that prenatal stress is unique and distinct from these models.…”