Decidual Neutrophil Infiltration Is Not Required for Preterm Birth in a Mouse Model of Infection-Induced Preterm Labor

Abstract

Parturition is associated with a leukocyte influx into the intrauterine tissues; however, the exact role these leukocytes play in the onset of labor remains unclear. Neutrophil infiltration of the uteroplacental tissues has been particularly associated with infection-associated preterm labor (PTL) in both women and mouse models. In this study, we investigated the role of neutrophils in a mouse model of infection-induced PTL. Intrauterine administration of LPS on day 17 of gestation resulted in a 7-fold increase in the number of decidual neutrophils compared with control mice receiving PBS (p < 0.01; n = 8–11). We hypothesized that neutrophil influx is necessary for PTL and that neutrophil depletion would abolish preterm birth. To test this hypothesis, mice were depleted of neutrophils by treatment with anti–Gr-1, anti–Ly-6G, or the appropriate IgG control Ab on day 16 of gestation prior to LPS on day 17 (n = 6–7). Successful neutrophil depletion was confirmed by flow cytometry and immunohistochemistry. Neutrophil depletion with Gr-1 resulted in reduced uterine and placental Il-1β expression (p < 0.05). Neutrophil depletion with Ly-6G reduced uterine Il-1β and Tnf-α expression (p < 0.05). However, neutrophil depletion with either Ab did not delay LPS-induced preterm birth. Collectively, these data show that decidual neutrophil infiltration is not essential for the induction of infection-induced PTL in the mouse, but that neutrophils contribute to the LPS-induced inflammatory response of the uteroplacental tissues.

Myometrial cytokines and their role in the onset of labour

“…Lye and coworkers found that pre-treatment with a non-specific chemokine antagonist delayed labour onset in association with a reduced inflammatory infiltration , suggesting that the inflammatory infiltration is important in inflammation-induced labour onset. Indeed, macrophage depletion prevents LPSinduced PTL in pregnant mice (Gonzalez et al 2011), but neutrophil depletion had no effect (Rinaldi et al 2014). These data suggest that macrophages but not neutrophils are important for this process.…”

The response of the innate immune and cardiovascular systems to LPS in pregnant and nonpregnant mice†

“…administration of LPS to determine an optimal dose of LPS, the latency to labor, and pup survival after injection on E16 as end points (Supplementary Table S3). Previously, we and others have used intrauterine LPS to reliably induce preterm labor [31], but the hemodynamic impact of LPS administration in pregnancy has not been assessed. Time to labor and pup survival were assessed in a vehicle (PBS) group and demonstrated no difference to untreated control data in our group (mean time to delivery in PBS-treated group 57.2 ± 6.6 compared with untreated group 55.6 ± 0.8).…”

An imbalance between innate and adaptive immune cells at the maternal–fetal interface occurs prior to endotoxin-induced preterm birth

“…22 However, the role of neutrophils remains unclear because their depletion does not prevent PTB in mice treated with endotoxin. 23 Macrophages also participate in the immunological mechanisms that lead to endotoxin-induced PTB as their depletion restores parturition on time. 24 Both macrophages and neutrophils are classically known as sources of pro-inflammatory cytokines at the maternal-fetal interface during labor at term and preterm stages.…”