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

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Abstract

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 ([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 messages

  • 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.

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Acknowledgements

We thank Ms. Sophie Ndagijimana for her technical assistance.

Funding

This work is financially supported by the Institut National de la Santé et de la Recherche Médicale (U1036), University Grenoble-Alpes, Commissariat à l’Energie Atomique (DSV/iRTSV/BCI), Région Auvergne-Rhône-Alpes “CLARA,” Ligue Nationale contre le Cancer and Ligue Départementale (Isère), and Fondation pour la recherche Médicale (FRM) SPF20150934074.

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Author notes

  1. P. Murthi and Nadia Alfaidy contributed equally to this work.

Authors and Affiliations

  1. Institut National de la Santé et de la Recherche Médicale, Unité 1036, Grenoble, France

    R. Abi Nahed, D. Reynaud, W. Traboulsi, S. Brouillet & Nadia Alfaidy

  2. Université Grenoble-Alpes, 38000, Grenoble, France

    R. Abi Nahed, D. Reynaud, W. Traboulsi, A. Wetzel, S. Brouillet, M. Benharouga & Nadia Alfaidy

  3. Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA), Biosciences and Biotechnology Institute of Grenoble, Grenoble, France

    R. Abi Nahed, D. Reynaud, W. Traboulsi, M. Benharouga & Nadia Alfaidy

  4. Department of Medicine, School of Clinical Sciences, Monash University and the Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria, Australia

    A. J. Borg & P. Murthi

  5. Department of Maternal-Fetal Medicine, Pregnancy Research Centre, The Royal Women’s Hospital, Parkville, Victoria, Australia

    A. J. Borg & P. Murthi

  6. Hôpital Couple-Enfant, Centre Clinique et Biologique d’Assistance Médicale à la Procréation-CECOS, Centre Hospitalier Universitaire de Grenoble, 38700, La Tronche, France

    A. Wetzel & S. Brouillet

  7. GReD, UMR CNRS 6293 INSERM 1103 Université Clermont Auvergne, CRBC, UFR de Médecine et des Professions Paramédicales, 63000, Clermont-Ferrand, France

    V. Sapin

  8. GIG - EA 7404 Université de Versailles-Saint-Quentin-en-Yvelines, Université Paris-Saclay, Unité de Formation et de Recherche des Sciences de la Santé Simone Veil, Montigny-le-Bretonneux, France

    M. N. Dieudonné

  9. Institut National de la Santé et de la Recherche Médicale, Unité 1179, Montigny-Le-Bretonneux, France

    M. Dakouane-Giudicelli

  10. Unité Mixte de Recherche 5249, Laboratoire de Chimie et Biologie des Métaux, Centre National de la Recherche Scientifique, Grenoble, France

    M. Benharouga

  11. Department of Obstetrics and Gynaecology, The University of Melbourne, Parkville, Victoria, Australia

    P. Murthi

  12. Unité INSERM U1036, Laboratoire BCI –BIG, CEA Grenoble 17, rue des Martyrs, 38054, Grenoble cedex 9, France

    Nadia Alfaidy

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  1. R. Abi Nahed
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  2. D. Reynaud
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Correspondence to Nadia Alfaidy.

Ethics declarations

Collection and processing of human placentas were approved by the local hospital ethical committees. All procedures were conducted in accordance with the Helsinki Declaration of 1975. All patients gave fully informed consent to participate in the research, and the institutional review board approved this investigation. These institutions were represented by the CCPP no. 1508520v0 (Comité Consultatif de Protection des Personnes) protocol 01-78 and by the Royal women’s hospital human and research ethics committee.

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Fig. S1: Panel A reports the specificity of the NLRP7 antibody. The blot in (a) shows the 100 KDa band corresponding the NLRP7 protein in HTR8/SVneo cells. The blot in (b) shows that the band corresponding to 100 KDa disappeared in the presence of the antigenic peptide used at 20 times the concentration of NLRP7 antibody used in all experiments. Fig. S2: Effects of NLRP7 activation or silencing on IL-1β and IL-18 expression and secretion in HTR8/SVneo. Panels A-B reports the effects of NLRP7 activation using FSL-1 on the secretion and production of IL-1β. Panel B reports the effects of NLRP7 activation using FSL-1 on the secretion of IL-18. Panel D and E report mRNA expression of IL1-B and IL-18 upon NLRP7 inactivation in HTR8/SVneo cells (n = 6). Data represent the mean ± SD. (**P < 0.01). Fig. S3: Validation of siRNA strategy in HTR8/SVneo, BeWo, primary cultures and placental explants: Panel A-B report the effects NLRP7 siRNA transfection in HTR8/SVneo cells on the expression of NLRP7 mRNA and protein, respectively. Panel C-D report the effects NLRP7 siRNA transfection in BeWo cells on the expression of NLRP7 mRNA and protein, respectively. Panel E-F report the effects NLRP7 siRNA transfection in primary trophoblast culture on the expression of NLRP7 mRNA and protein, respectively. Panel G-H report the effects NLRP7 siRNA transfection in placental explants on the expression of NLRP7 mRNA and protein, respectively. Data represent the mean ± SD. All experiments were performed at least three times. Fig. S4: Panel A. reports primary trophoblast syncytialisation in Scrambled siRNA (a) and NLRP7 siRNA (b) conditions. Panel B reports a comparison of syncytialisation of BeWo cells in Scrambled siRNA (a) and NLRP7 siRNA (b) using the desmoplakin immuno-staining. Panel C reports a blot that illustrates the activation of caspase-1 upon the specific activation of the NLRP7 inflammasome in the HTR8/SVneo, using FSL-1. Fig. S5: Cytokine array comparison of conditioned media collected from Scrambled siRNA and NLRP7 siRNA. Panel A reports a graph of global analysis of 54 cytokines assessed in Scrambled siRNA and NLRP7 siRNA treated BeWo cells. Blue arrows indicate the cytokine that have been significantly deregulated upon NLRP7 inhibition and are associated with trophoblast invasion. Panel B reports the validation of the IGF-II, VEGF-R2 and prolactin at the mRNA levels using RT-qPCR (n = 3). Data represent the mean ± SD. (PDF 402 kb)

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Abi Nahed, R., Reynaud, D., Borg, A.J. et al. NLRP7 is increased in human idiopathic fetal growth restriction and plays a critical role in trophoblast differentiation. J Mol Med 97, 355–367 (2019). https://doi.org/10.1007/s00109-018-01737-x

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