Heterogeneity in Inflammatory Responses to Endotoxin at the Feto-Maternal Interface

Transcriptomic profiling was performed to assess differentially expressed genes and pathway enrichment. Inflammatory cytokines were quantified using multiplex immunoassays. Protein-level responses were validated using western blotting.

Regulatory network analysis identified upstream drivers of cell-specific responses. LPS induced a robust and uniform inflammatory response in DECs, marked by high expression of pro-inflammatory chemokines, and prostaglandin biosynthesis enzymes associated with adverse pregnancy outcomes. In contrast, CTCs showed an attenuated response, characterized by selective induction of stress-associated genes with minimal activation of classical inflammatory pathways.

Transcriptomic network analysis revealed distinct cell-type-specific regulatory hubs, including STAT1 and IRF7 in DECs and RELA and MYD88 in CTCs. Notably, DECs also activated anti-inflammatory signaling and pyroptosis-related pathways, which were largely absent in CTCs, indicating compartmentalized immune regulation at the feto-maternal interface. Our findings reveal a fundamental heterogeneity in inflammatory responses at the FMi, with maternal cells exhibiting greater sensitivity to endotoxin-induced activation compared to fetal chorion trophoblast cells.

These differential reactivity responses may be an evolved mechanism to shield the fetus from excessive inflammation or to impede the inflammatory onslaught from reaching the fetus. Understanding cell-specific responses provides a foundation for understanding tolerance and mediators of intolerance at the FMi and identifying potential targets for therapeutic strategies in inflammation-associated pregnancy complications.