Decidua macrophages display a restrained inflammatory profile during chorioamnionitis

Introduction: Decidual macrophages (DMs) are strategically located at the maternal-fetal interface to orchestrate innate host defense while balancing tolerance to the allogenic fetus. An important pregnancy complication is chorioamnionitis characterized by infection/inflammation in the fetal membranes and the amniotic fluid with upregulation of TNFα and other pro-inflammatory cytokines. The goal of this study was to determine maternal vs fetal origin of DMs and to investigate whether TNF signaling play a role in DM response to chorioamnionitis. Methods: Decidua tissue from pregnant Rhesus macaques given intraamniotic injection of lipopolysaccharide/saline with or without the TNF inhibitor Adalimumab (n=33) and human subjects with/out chorioamnionitis (n=11) were used for bulk RNAseq, scRNAseq, and flow cytometry experiments. Results: In both human and Rhesus macaques, DMs coordinately upregulate both pro- and anti-inflammatory cytokines during chorioamnionitis. Although DMs did not express TNF during chorioamnionitis, inhibition of TNF signaling downregulated 50% of LPS induced genes. About 4% of the DMs were of male fetus origin. These fetal origin DMs selectively upregulated IL6 mRNA during chorioamnionitis, suggesting a potential role in fetal immune priming. Discussion: We suggest that DMs orchestrate a carefully balanced host defense with a restrained pro-inflammatory profile during chorioamnionitis to potentially prevent adverse outcomes while protecting the mother-fetus dyad. Activation of fetal origin macrophages during chorioamnionitis may have implications for shaping neonatal immune responses.