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

Abstract

Problem 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. Method of study Pregnant mice were treated with intraperitoneal injections of IL‐1β (0, 0.1, 0.5, or 1 μg) from embryonic day (E)14 to E17. Placenta and fetal brains were harvested and analyzed for morphologic changes and IL‐1β signaling markers. Results 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 1 μg 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. Conclusion This work demonstrates that systemic IL‐1β injection causes dose‐dependent structural and functional changes in the placenta and fetal brain.

Dysregulated immunity in SARS-CoV-2 infected pregnant women

“…We assayed cytokine mRNA expression during SARS-CoV-2 infection as a biomarker for inflammation. Because IL-1β activation during pregnancy can cause adverse fetal outcomes 2,14,15 , we measured IL1β mRNA expression in maternal blood, cord blood, and the maternal and fetal sides of placentas, which did not differ between SARS-CoV-2 positive and negative pregnant women ( Figure 1A-D ). To test whether IL1β expression differed as a function of maternal symptoms, samples were further categorized based on whether pregnant women were asymptomatic, symptomatic, or SARS-CoV-2 negative.…”

Pregnancy alters interleukin-1 beta expression and antiviral antibody responses during severe acute respiratory syndrome coronavirus 2 infection

“…2,10,11 We assayed cytokine mRNA expression during SARS-CoV-2 infection as a biomarker for inflammation. Because IL-1b activation during pregnancy can cause adverse fetal outcomes, 2,19,20 we measured IL-1b mRNA expression in maternal blood (total, 27; positive, 18; negative, 9), cord blood (total, 29; positive, 20; negative, 9), and the maternal (total, 11; positive, 8; negative, 1) and fetal (total, 26; positive, 19; negative, 7) sides of the placentas, which did not differ between pregnant women with and without SARS-CoV-2 infection (Figure 1, AeD). To assess whether the expression of IL-1b differed depending on the number of days between a…”

SARS‐CoV2 and pregnancy: An invisible enemy?

“…20 Taken together, the cytokine storm (pro-inflammatory cytokines) induced by SARS-CoV-2 might place pregnant women at greater risk by causing an increased pro-inflammatory state with the potential to impact fetal brain development; thus, increasing the risk for autism, mental health disorders or schizophrenia. 26,[32][33][34] Currently, there are no studies reported on decidual immune cell interactions with SARS-CoV-2, but there are studies on the effect of SARS-CoV-2 on peripheral blood leukocytes. One key difference noted in peripheral blood leukocytes from those suffering severe COVID-19 symptoms, versus those with mild symptoms, was a decrease in IFN-γ and TNF-α in CD4+ T cells from the severe symptoms group.…”

“…A recent systematic review identified increased level of C‐reactive protein (CRP) in a majority of COVID‐19 positive pregnant women 20 . Taken together, the cytokine storm (pro‐inflammatory cytokines) induced by SARS‐CoV‐2 might place pregnant women at greater risk by causing an increased pro‐inflammatory state with the potential to impact fetal brain development; thus, increasing the risk for autism, mental health disorders or schizophrenia 26,32‐34 …”