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

Authors
  • Abi Nahed, R.1, 2, 3
  • Reynaud, D.1, 2, 3
  • Borg, A. J.4, 5
  • Traboulsi, W.1, 2, 3
  • Wetzel, A.2, 6
  • Sapin, V.7
  • Brouillet, S.1, 2, 6
  • Dieudonné, M. N.8
  • Dakouane-Giudicelli, M.9
  • Benharouga, M.2, 3, 10
  • Murthi, P.4, 5, 11
  • Alfaidy, Nadia1, 2, 3, 12
  • 1 Institut National de la Santé et de la Recherche Médicale, Unité 1036, Grenoble, France , Grenoble (France)
  • 2 Université Grenoble-Alpes, Grenoble, 38000, France , Grenoble (France)
  • 3 Biosciences and Biotechnology Institute of Grenoble, Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA), Grenoble, France , Grenoble (France)
  • 4 Monash University and the Ritchie Centre, Hudson Institute of Medical Research, Department of Medicine, School of Clinical Sciences, Clayton, Victoria, Australia , Clayton (Australia)
  • 5 The Royal Women’s Hospital, Department of Maternal-Fetal Medicine, Pregnancy Research Centre, Parkville, Victoria, Australia , Parkville (Australia)
  • 6 Centre Hospitalier Universitaire de Grenoble, Hôpital Couple-Enfant, Centre Clinique et Biologique d’Assistance Médicale à la Procréation-CECOS, La Tronche, 38700, France , La Tronche (France)
  • 7 CRBC, UFR de Médecine et des Professions Paramédicales, GReD, UMR CNRS 6293 INSERM 1103 Université Clermont Auvergne, Clermont-Ferrand, 63000, France , Clermont-Ferrand (France)
  • 8 Université Paris-Saclay, Unité de Formation et de Recherche des Sciences de la Santé Simone Veil, GIG - EA 7404 Université de Versailles-Saint-Quentin-en-Yvelines, Montigny-le-Bretonneux, France , Montigny-le-Bretonneux (France)
  • 9 Institut National de la Santé et de la Recherche Médicale, Unité 1179, Montigny-Le-Bretonneux, France , Montigny-Le-Bretonneux (France)
  • 10 Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5249, Laboratoire de Chimie et Biologie des Métaux, Grenoble, France , Grenoble (France)
  • 11 The University of Melbourne, Department of Obstetrics and Gynaecology, Parkville, Victoria, Australia , Parkville (Australia)
  • 12 Unité INSERM U1036, Laboratoire BCI –BIG, CEA Grenoble 17, rue des Martyrs, Grenoble cedex 9, 38054, France , Grenoble cedex 9 (France)
Type
Published Article
Journal
Journal of Molecular Medicine
Publisher
Springer-Verlag
Publication Date
Jan 08, 2019
Volume
97
Issue
3
Pages
355–367
Identifiers
DOI: 10.1007/s00109-018-01737-x
Source
Springer Nature
Keywords
License
Yellow

Abstract

AbstractFetal 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 ([3H]-thymidine) and controls the precocious differentiation of trophoblasts towards syncytium (syncytin 1 and 2 and β-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-1β, but not IL-18 secretion. In relation to the FGR, we demonstrated that major components of NLRP7 inflammasome machinery are increased and that IL-1β 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.

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