Abstract
Infection-driven inflammation in pregnancy is a major cause of spontaneous preterm birth (PTB). Both systemic infection and bacterial ascension through the vagina/cervix to the amniotic cavity are strongly associated with PTB. However, the contribution of maternal or fetal inflammatory responses in the context of systemic or localized models of infection-driven PTB is not well defined. Here, using intraperitoneal or intraamniotic LPS challenge, we examined the necessity and sufficiency of maternal and fetal Toll-like receptor (TLR) 4 signaling in induction of inflammatory vigor and PTB. Both systemic and local LPS challenge promoted induction of inflammatory pathways in uteroplacental tissues and induced PTB. Restriction of TLR4 expression to the maternal compartment was sufficient for induction of LPS-driven PTB in either systemic or intraamniotic challenge models. In contrast, restriction of TLR4 expression to the fetal compartment failed to induce LPS-driven PTB. Vav1-Cre–mediated genetic deletion of TLR4 suggested a critical role for maternal immune cells in inflammation-driven PTB. Further, passive transfer of WT in vitro–derived macrophages and dendritic cells to TLR4-null gravid females was sufficient to induce an inflammatory response and drive PTB. Cumulatively, these findings highlight the critical role for maternal regulation of inflammatory cues in induction of inflammation-driven parturition.
Highlights
Preterm birth (PTB), the leading cause of neonatal morbidity and mortality, remains a major public health problem [1, 2]
Interpretation of reduction studies focused on better understanding of LPS-driven immune activation has been complicated by the use of variable and impure reagents (e.g., “LPS” containing other Toll-like receptor (TLR) ligands capable of inducing an immune response in the absence of TLR4 or endogenous ligands that are contaminated by LPS) [37]
These findings suggested that LPS purity and the quality and strength of the subsequent inflammatory response might impact induction of PTB in vivo
Summary
Preterm birth (PTB), the leading cause of neonatal morbidity and mortality, remains a major public health problem [1, 2]. Infection and infection-driven activation of inflammatory responses are thought to be a major cause of “spontaneous” PTB [1, 2, 6]. Infection can occur systemically (e.g., listeriosis, influenza, sepsis) or be localized to the intrauterine or intraamniotic compartments (e.g., ascending bacterial infection) [7, 8]. Infection and infection-associated inflammation can regulate the timing of parturition [6]. Despite the significant impact of PTB on human health and recognition of infection as a predisposing factor, the cellular and molecular mechanisms underlying inflammation-driven PTB remain undefined [9]
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