Homeostatic Type I IFN Response at the Placenta Contributes to Sex-biased Neurodevelopmental Outcome

초록

The maternal-fetal interface, placenta, plays pivotal roles in fetal development. Recent evidence shows that the placenta contributes to the sex-biased prevalence of some developmental disorders such as neurodevelopmental disorders. Commencing an exploration into the molecular intricacies of fetal sex-specific transcriptional changes within the placenta, our study leveraged single-cell RNA sequencing. We uncovered a diminished expression of interferon (IFN)-responsive genes (ISGs) in male fetus-associated trophoblasts compared to female, which have pivotal roles in the process of spiral artery remodeling. We further found maternal NK cells associated with male fetus placenta showed a reduction in the interferon production pathway. The introduction of maternal immune activation (MIA), which induces neurodevelopmental abnormalities in male offspring, it reversed these sex-specific disparities in the placenta. In pursuit of unraveling the potential link between sex-specific ISGs expression and neurodevelopmental outcomes in MIA offspring, we selectively removed IFN alpha and beta receptor subunit 1 (IFNAR1) in a trophoblast-specific manner. Blunting IFNAR1 in the placenta protected male offspring from MIA-induced behavioral abnormalities. Our data suggests the intricate landscape of sex-specific IFN response at the maternal-fetal interface and underscore its role in shaping the sex-bias observed in MIA-induced neurodevelopmental phenotypes.