NLRP7 is increased in human idiopathic fetal growth restriction and plays a critical role in trophoblast differentiation

Fetal growth restriction (FGR) the leading cause of perinatal mortality and morbidity is highly related to abnormal placental development, and placentas from FGR pregnancies are often characterized by increased inflammation. However, the mechanisms of FGR-associated inflammation are far from being understood. NLRP7, a member of a family of receptors involved in the innate immune responses, has been shown to be associated with gestational trophoblastic diseases. Here, we characterized the expression and the functional role of NLRP7 in the placenta and investigated its involvement in the pathogenesis of FGR. We used primary trophoblasts and placental explants that were collected during early pregnancy, and established trophoblast-derived cell lines, human placental villi, and serum samples from early pregnancy (n=38) and from FGR (n=40) and age-matched controls (n=32). Our results show that NLRP7 (i) is predominantly expressed in the trophoblasts during the hypoxic period of placental development and its expression is upregulated by hypoxia and (ii) increases trophoblast proliferation ([H-3]-thymidine) and controls the precocious differentiation of trophoblasts towards syncytium (syncytin 1 and 2 and -hCG production and xCELLigence analysis) and towards invasive extravillous trophoblast (2D and 3D cultures). We have also demonstrated that NLRP7 inflammasome activation in trophoblast cells increases IL-1, but not IL-18 secretion. In relation to the FGR, we demonstrated that major components of NLRP7 inflammasome machinery are increased and that IL-1 but not IL-18 circulating levels are increased in FGR. Altogether, our results identified NLRP7 as a critical placental factor and provided evidence for its deregulation in FGR. NLRP7 inflammasome is abundantly expressed by trophoblast cells. It is regulated by a key parameter of placental development, hypoxia. It controls trophoblast proliferation, migration, and invasion and exhibits anti-apoptotic role. NLRP7 machinery is deregulated in FGR pregnancies.Key messagesNLRP7 inflammasome is abundantly expressed by trophoblast cells.It is regulated by a key parameter of placental development, hypoxia.It controls trophoblast proliferation, migration, and invasion and exhibits anti-apoptotic role.NLRP7 machinery is deregulated in FGR pregnancies.