Maternal regulation of inflammatory cues is required for induction of preterm birth
Monica Cappelletti, Jessica R. Doll, Traci E. Stankiewicz, Matthew J. Lawson, Vivien Sauer, Bingqiang Wen, Vladimir V. Kalinichenko, Xiaofei Sun, Tamara Tilburgs, Senad Divanovic
Monica Cappelletti, Jessica R. Doll, Traci E. Stankiewicz, Matthew J. Lawson, Vivien Sauer, Bingqiang Wen, Vladimir V. Kalinichenko, Xiaofei Sun, Tamara Tilburgs, Senad Divanovic
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Research Article Inflammation

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

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.

Authors

Monica Cappelletti, Jessica R. Doll, Traci E. Stankiewicz, Matthew J. Lawson, Vivien Sauer, Bingqiang Wen, Vladimir V. Kalinichenko, Xiaofei Sun, Tamara Tilburgs, Senad Divanovic

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Figure 2

Maternal TLR4 expression is required to induce preterm birth.

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Maternal TLR4 expression is required to induce preterm birth. (A) MEFs (...
(A) MEFs (n = 3/condition) were isolated on day 13 of pregnancy, and the IL-6 response to ultrapure LPS was measured in WT, TLR4-heterozygous, and TLR4-knockout cells. Data represent average ± SEM. (B) IL-6 levels in the serum and amniotic fluid of WT mice 6 hours after i.p. or i.a. administration of LPS (75 μg or 5 μg, respectively) or saline on day 16 of pregnancy (n = 3/condition). Cytokines were measured in pooled amniotic fluid for each uterine horn and graphed as the average amount per pregnancy. Data represent average ± SEM. (C) Endotoxin levels in amniotic fluid of WT mice 6 hours after i.p. or i.a. administration of LPS (75 μg or 5 μg, respectively) or saline on day 16 of pregnancy (n = 3–4/condition). Amniotic fluid was pooled for each uterine horn and graphed as the average amount per pregnancy. Data represent average ± SEM. (D) Levels of serum IL-6 and TNF determined by in vivo cytokine capture assay (IVCCA) in adult WT, TLR4-heterozygous, and TLR4-knockout mice following i.p. injection with ultrapure LPS (n = 3–5/condition). Data represent average ± SEM. (E) Gravid WT and TLR4-knockout mice (n = 3–7/condition) carrying heterozygous pups were treated at day 16 of pregnancy with i.p. or i.a. ultrapure LPS and instance of PTB was quantified. χ2 (2 × 4 matrix) P = 0.0004. (A–D) ANOVA followed by Tukey’s correction. **P < 0.01, ***P < 0.001, ****P < 0.0001.