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 4

Activation of TLR4 on immune cells contributes to preterm birth.

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Activation of TLR4 on immune cells contributes to preterm birth. (A) Gra...
(A) Gravid TLR4fl/fl Vav1-Cre and WT female mice (n = 5–8/condition) were challenged i.p. with 75 μg ultrapure LPS at day 16 of pregnancy and instances of PTB were quantified. Fisher’s exact test P = 0.0002. (B) TLR4–/– mice received WT in vitro–derived macrophages and dendritic cells by passive transfer (n = 2–5/condition) as indicated, and 2 hours later mice were challenged with 75 μg ultrapure LPS or saline. Serum levels of IL-6 and TNF were measured by IVCCA. Data represent average ± SEM. ANOVA **P < 0.01, ***P < 0.001, ****P < 0.0001. (C) TLR4–/– mice received 150 × 106 WT in vitro–derived macrophages and dendritic cells by passive transfer (n = 3), and 2 hours later mice were challenged with 75 μg ultrapure LPS alongside WT controls (n = 6). Serum levels of IL-6 and TNF were measured by IVCCA. (D) Gravid TLR4–/– mice received 150 × 106 WT in vitro–derived macrophages and dendritic cells by passive transfer (n = 5) on day 16 of pregnancy and 2 hours later were challenged with 75 μg ultrapure LPS alongside gravid TLR4–/– controls (n = 5). Instances of PTB were quantified. Fisher’s exact test P = 0.0476. (E) Gravid TLR4fl/fl LysM-Cre, TLR4fl/fl CD11c-Cre, and WT female mice (n = 7–9/condition) were treated with LPS at day 16 of pregnancy and instances of PTB were quantified. χ2 P = 0.1244. (F) WT, TLR4fl/fl Vav1-Cre, TLR4fl/fl LysM-Cre, and TLR4fl/fl CD11c-Cre mice were treated with ultrapure LPS and serum levels of IL-6 and TNF were measured by IVCCA (n = 3–5/condition). Data represent average ± SEM. ANOVA of each Cre+ condition compared with Cre– followed by Tukey’s correction. ****P < 0.001.