J Immunol. 2026 Mar 17;215(3):vkag014. doi: 10.1093/jimmun/vkag014.
ABSTRACT
The fetomaternal interface (FMi), comprising fetal chorionic trophoblast cells (CTCs) and maternal decidual stromal cells (DECs), plays a critical role in providing immune tolerance during pregnancy. Intrauterine inflammation is major trigger of adverse outcomes such as preterm birth, yet the cell-specific inflammatory responses at the FMi -; poorly defined. We investigated differential inflammatory responses of fetal and maternal cell populations at the FMi upon exposure to endotoxin (lipopolysaccharide [LPS]). Primary CTCs and DECs were isolated from human term fetal membrane tissues. Cells were treated with LPS (100 ng/mL, 48 h. Transcriptomic profiling, multiplex immunoassays and western blotting was performed. Regulatory network analysis identified upstream drivers of cell-specific responses. LPS induced a pronounced inflammatory response in DECs, marked by high expression of proinflammatory chemokines, and prostaglandin enzymes associated with adverse pregnancy outcomes. In contrast, CTCs exhibited attenuated response, characterized by selective induction of stress-associated genes with minimal activation of inflammatory pathways. Network analysis revealed distinct cell type-specific regulatory hubs, including STAT1 and IRF7 in DECs and RELA and MYD88 in CTCs. DECs also activated anti-inflammatory signaling and pyroptosis-related pathways, which were largely absent in CTCs, indicating compartmentalized immune regulation Our findings demonstrate fundamental heterogeneity in inflammatory responses at the FMi, with maternal cells exhibiting greater sensitivity to endotoxin-induced activation compared with fetal CTCs. These differential responses may protect the fetus from excessive inflammation. 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.
PMID:41847862 | DOI:10.1093/jimmun/vkag014