The human placenta mediates maternal–fetal exchanges while maintaining pregnancy. Its development relies on several critical steps, including uterine invasion by extravillous cytotrophoblasts (EVCTs). These cells anchor the chorionic villi to the uterine wall, participate in the remodeling of the maternal spiral arteries, and contribute to immune tolerance of the conceptus. Defective trophoblast invasion is associated with complications such as miscarriage, intrauterine growth restriction, and preeclampsia. However, many pregnancy disorders result from infections, whose deleterious effects appear to be mediated by elevated inflammatory factors in the maternal circulation, particularly type I interferons. The response to these infections is accompanied by the induction of interferon-inducible transmembrane proteins (IFITMs), known as restriction factors that block the entry of numerous viruses into cells and whose inhibitory effect on syncytiotrophoblast formation had previously been described.
The authors asked whether these proteins also affected EVCT invasion, a question that had not been investigated until then. To address it, they combined several models: the HTR8/SVneo cell line, primary EVCTs, and first-trimester placental explants cultured in vitro and ex vivo, mice treated in vivo with poly(I:C), an interferon inducer, as well as sections of pathological human placentas. Invasive capacity was measured using cell migration assays monitored by real-time imaging, while protein expression was assessed by immunostaining and western blot. Lentiviral transduction experiments were used to specifically introduce IFITM1, IFITM2, or IFITM3 in order to isolate their respective contributions.
Cells exposed to interferon-β showed increased IFITM expression accompanied by a reduction in their invasive capacities. The transduction experiments confirmed that IFITM1 in particular contributed to this decreased invasion. In mice, the migration of trophoblast giant cells, the murine equivalent of human EVCTs, was significantly reduced after poly(I:C) treatment. Finally, the analysis of human placentas infected with cytomegalovirus (CMV) or bacteria revealed IFITM1 overexpression in EVCTs.
This work establishes that elevated IFITM1 levels impair trophoblast invasion. The authors propose that this mechanism could contribute to the placental dysfunctions associated with interferon-mediated disorders, linking infection-driven inflammation to abnormalities of placental development.