Fibrinoid-associated neutrophils promote invasive placentation and neutrophil reprogramming at the maternal-fetal...

Successful early pregnancy depends on coordinated interactions between the placenta and maternal immune cells, but the mechanisms underlying this interplay remain incompletely understood. Placenta-derived extravillous trophoblasts (EVTs) invade the decidua basalis and remodel maternal vessels, yet the contribution of neutrophils to this process is unclear. Here, we analyzed first-trimester human decidual tissue together with blood samples and identified decidual fibrinoid-associated neutrophils (dFANs) localized to Rohr's layer, a fibrinoid matrix between the decidua proper and the intervillous space. Flow cytometry and mass cytometry showed that dFANs differ phenotypically from donor-matched peripheral blood neutrophils (PBNs). Functionally, dFANs secreted high levels of matrix metalloproteinase-9 (MMP-9) and promoted EVT invasion, whereas PBNs induced EVT apoptosis. dFAN-derived MMP-9 enhanced activation of latent transforming growth factor-β (TGF-β), which suppressed PBN cytotoxicity and shifted PBNs toward an MMP-9-hypersecretory, proinvasive state. These findings define a dFAN-dependent MMP-9-TGF-β axis that supports invasive placentation at the maternal-fetal interface.