1. Peroxisomal defects in microglial cells induce a disease-associated microglial signature
- Author
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Quentin Raas, Ali Tawbeh, Mounia Tahri-Joutey, Catherine Gondcaille, Céline Keime, Romain Kaiser, Doriane Trompier, Boubker Nasser, Valerio Leoni, Emma Bellanger, Maud Boussand, Yannick Hamon, Alexandre Benani, Francesca Di Cara, Caroline Truntzer, Mustapha Cherkaoui-Malki, Pierre Andreoletti, Stéphane Savary, Raas, Q, Tawbeh, A, Tahri-Joutey, M, Gondcaille, C, Keime, C, Kaiser, R, Trompier, D, Nasser, B, Leoni, V, Bellanger, E, Boussand, M, Hamon, Y, Benani, A, Di Cara, F, Truntzer, C, Cherkaoui-Malki, M, Andreoletti, P, Savary, S, Laboratoire Bio-PeroxIL. Biochimie du peroxysome, inflammation et métabolisme lipidique [Dijon] (BIO-PEROXIL), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Faculty of Science and Technology, University Hassan I, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Università degli Studi di Milano-Bicocca = University of Milano-Bicocca (UNIMIB), Mi-mAbs (C/O CIML), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Université de Bourgogne (UB)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Université Bourgogne Franche-Comté [COMUE] (UBFC), Dalhousie University [Halifax], Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER, We warmly acknowledge the Fondation Maladies Rares which supported our transcriptomic analysis project (GenOmics: High throughput sequencing and rare diseases, call 2017-20170615). Sequencing was performed by the GenomEast platform, a member of the 'France Génomique' consortium (ANR-10-INBS-0009). We would like to acknowledge the SATT Sayens of Dijon, the CHU of Dijon (project CRBSEP-EMATSEP grant), the Canadian New Frontiers Research Funds Exploration (NFRF-E 19-00007), and the regional council of Bourgogne Franche-Comté (Project PERSIL 2019) for their support. We are also grateful to networking support by the COST Action CA 16,112 NutRedOx (Personalized Nutrition in aging society: redox control of major age-related diseases), supported by COST (European Cooperation in Science and Technology). We thank the Centre d’Immunologie de Marseille-Luminy (CIML) flow cytometry facility. This work was supported by institutional grants from INSERM, CNRS and Aix-Marseille University to the CIML and program grant from the French National Research Agency (ANR-17-CE15-0032). The project leading to this publication has received funding from Excellence Initiative of Aix-Marseille University—A*MIDEX, a French 'Investissements d’Avenir' program. The laboratory BioPeroxIL was funded by the Ministère de l’Education Nationale et de l’Enseignement Supérieur et de la Recherche (France) and by the University of Bourgogne. MT-J was funded by CNRST (PhD excellence grant number: 17UHP2019, Morocco) and by the Action Intégrée of the Comité Mixte Inter-universitaire Franco-Marocain (n° TBK 19/92 n° Campus France: 41501RJ) from the PHC Toubkal program, Ministère des Affaires Étrangères., ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), and ANR-17-CE15-0032,NanoGammaR,Comprendre comment la dynamique membranaire du récepteur à l'IFN-gamma à l'échelle nanométrique contrôle les réponses immunes médiées par l'IFN-gamma(2017)
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Cellular and Molecular Neuroscience ,autophagy ,[SCCO.NEUR]Cognitive science/Neuroscience ,lipid metabolism ,[SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO] ,adrenoleukodystrophy (X-ALD) ,lysosome ,microglia ,peroxisome ,Molecular Biology - Abstract
International audience; Microglial cells ensure essential roles in brain homeostasis. In pathological condition, microglia adopt a common signature, called disease-associated microglial (DAM) signature, characterized by the loss of homeostatic genes and the induction of disease-associated genes. In X-linked adrenoleukodystrophy (X-ALD), the most common peroxisomal disease, microglial defect has been shown to precede myelin degradation and may actively contribute to the neurodegenerative process. We previously established BV-2 microglial cell models bearing mutations in peroxisomal genes that recapitulate some of the hallmarks of the peroxisomal β-oxidation defects such as very long-chain fatty acid (VLCFA) accumulation. In these cell lines, we used RNA-sequencing and identified large-scale reprogramming for genes involved in lipid metabolism, immune response, cell signaling, lysosome and autophagy, as well as a DAM-like signature. We highlighted cholesterol accumulation in plasma membranes and observed autophagy patterns in the cell mutants. We confirmed the upregulation or downregulation at the protein level for a few selected genes that mostly corroborated our observations and clearly demonstrated increased expression and secretion of DAM proteins in the BV-2 mutant cells. In conclusion, the peroxisomal defects in microglial cells not only impact on VLCFA metabolism but also force microglial cells to adopt a pathological phenotype likely representing a key contributor to the pathogenesis of peroxisomal disorders.
- Published
- 2023