(17) Inflammation at the Maternal-fetal Interface Alters the Immunological Landscape in a Mouse Model of Ascending Chorioamnionitis

Background: A successful pregnancy requires a state of immunotolerance in-utero, to prevent maternal rejection of the semi-allogeneic fetus. Chorioamnionitis, defined as an infection and/or inflammation of the placenta and fetal membranes, disrupts this immunotolerant state to drive preterm birth (PTB) – a leading cause of neonatal and infant mortality and long-term morbidities.

Objectives: Current diagnostics for chorioamnionitis are limited as they primarily detect inflammation after it has triggered the irreversible process of labor. This highlights the need to identify strategies to prevent inflammation and sustain immune tolerance at the maternal-fetal interface (MFI) during pregnancy. While various immune cells at the MFI maintain this immunotolerant and anti-inflammatory state, the impact of chorioamnionitis on their number, phenotype and function remains poorly defined. Elucidating these mechanisms may reveal therapeutic targets to prevent PTB.

Design/Methods: To address this, we utilized a mouse model of ascending chorioamnionitis. Adult male and female C57BL/6 mice were time mated. At embryonic day 14.5 (E14.5), pregnant dams were intravaginally inoculated with 100 CFU of E. coli K1 or sterile PBS (control). Eighteen hours later, decidual tissues were obtained from each gestational sac and processed for flow cytometric analysis to profile immune cells; amniotic fluid (AF) was plated to quantify bacterial load and assessed for cytokine levels via a multiplexed protein assay.

Results: Compared to control (PBS) dams, E. coli-infected dams exhibited a robust inflammatory response, marked by high proinflammatory cytokine (CXCL1, MIP-1α, IL-1β, IL-6, TNF- α, CXCL10) levels in the AF and increased neutrophilic infiltration in the decidua. Additionally, decidual dendritic cells and macrophages from infected dams were more pro-inflammatory (Ly6Chi) and less tolerogenic (Ly6Clo). We also observed an increased frequency of activated decidual T cells (CD44hi) and a marked reduction in decidual Treg numbers in E. coli-infected dams.

Conclusions: These finding suggests that chorioamnionitis disrupts the immune homeostasis at the MFI, shifting immune cells from a tolerogenic phenotype to a more activated/pro-inflammatory phenotype. This shift likely drives the upregulation of pathways that contribute to early onset labor and ultimately PTB. Future studies will investigate how inflammation at the MFI impacts Tregs stability, including a potential shift to a pro-inflammatory “ex-Treg” phenotype.