Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
JCI Insight. 2020 Nov 19;5(22):138812. doi: 10.1172/jci.insight.138812.
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.
在妊娠期间，感染引发的炎症是自发性早产 (PTB) 的主要原因。全身性感染和细菌通过阴道/宫颈上升到羊膜腔都与 PTB 密切相关。然而，在感染性 PTB 的全身性或局部模型中，母体或胎儿炎症反应的贡献尚不清楚。在这里，我们使用腹膜内或羊膜内 LPS 挑战，研究了母体和胎儿 Toll 样受体 (TLR) 4 信号在诱导炎症活力和 PTB 中的必要性和充分性。全身和局部 LPS 挑战均促进了子宫胎盘组织中炎症途径的诱导，并导致了 PTB。TLR4 表达限制在母体隔室足以诱导全身性或羊膜内 LPS 挑战模型中的 LPS 驱动的 PTB。相比之下，TLR4 表达限制在胎儿隔室不足以诱导 LPS 驱动的 PTB。Vav1-Cre 介导的 TLR4 基因缺失表明母体免疫细胞在炎症驱动的 PTB 中起关键作用。此外，将 WT 体外衍生的巨噬细胞和树突状细胞被动转移到 TLR4 缺失的妊娠雌性中足以诱导炎症反应并导致 PTB。综上所述，这些发现强调了母体调节炎症信号在诱导炎症性分娩中的关键作用。
