The pro-inflammatory cytokines IFN-α and TNF-α inhibit extravillous trophoblast invasion

Impaired trophoblast differentiation and invasion are a hallmark of severe pregnancy complications such as preeclampsia and fetal growth restriction. Women with immune-mediated inflammatory diseases, in particular systemic lupus erythematosus (SLE), have an increased risk for adverse pregnancy outcomes. These diseases are characterized by high activity of pro-inflammatory cytokines, such as interferon alpha (IFN-α) and tumor necrosis factor alpha (TNF-α). Here, we investigated the direct effects of these cytokines on extravillous trophoblast (EVT) differentiation and invasion, using trophoblast stem cells (TSCs), trophoblast organoids, and first-trimester placental and decidual tissue. While neither cytokine impaired EVT differentiation, both significantly reduced EVT invasion into extracellular matrix and/or maternal decidua. Transcriptomic analysis revealed cytokine-induced alterations in gene expression associated with epithelial-mesenchymal transition (EMT), a key process in EVT invasion. These findings suggest that elevated IFN-α and TNF-α levels may directly impair placental development by inhibiting EVT invasion, providing a mechanistic link between inflammatory conditions such SLE and adverse pregnancy outcomes.