Dose-dependent structural and immunological changes in the placenta and fetal brain in response to systemic inflammation during pregnancy.

Abstract

Systemic maternal inflammation is associated with adverse neonatal sequelae. We tested the hypothesis that IL-1β is a key inflammatory regulator of adverse pregnancy outcomes. Pregnant mice were treated with intraperitoneal injections of IL-1β (0, 0.1, 0.5, or 1μg) from embryonic day (E)14 to E17. Placenta and fetal brains were harvested and analyzed for morphologic changes and IL-1β signaling markers. As compared with non-treated dams, maternal injections with IL-1β resulted in increased p-NF-κB and caspase-1 in placentas and fetal brains, but not consistently in spleens, suggesting induction of intrinsic IL-1β production. These findings were confirmed by increased levels of IL-1β in the placentas of the IL-1β-treated dams. Systemic treatment of dams with IL-1β suppressed Stat1 signaling. Maternal inflammation caused by IL-1β treatment reduced fetal viability to 80.6% and 58.9%, in dams treated with either 0.5 or 1μg of IL-1β, respectively. In the placentas, there was an IL-1β dose-dependent distortion of the labyrinth structure, decreased numbers of mononuclear trophoblast giant cells, and reduced proportions of endothelial cells as compared to placentas from control dams. In fetal brains collected at E17, there was an IL-1β dose-dependent reduction in cortical neuronal morphology. This work demonstrates that systemic IL-1β injection causes dose-dependent structural and functional changes in the placenta and fetal brain.