1. Predominant role of microglia in brain iron retention in Sanfilippo syndrome, a pediatric neurodegenerative disease
- Author
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Laurent Puy, Cathy Gomila, Jérôme Ausseil, Agnès Boullier, Zoubida Karim, Stéphanie Trudel, Christelle Lony, Sandrine Vitry, Thibaud Lefebvre, Walaa Darwiche, Vincent Puy, Université de Picardie Jules Verne (UPJV), North Hospital, Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Neuro-Immunologie Virale, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Inserm, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hospitalier universitaire d'Amiens (CHU Amiens-Picardie), CHU Amiens-Picardie, Mécanismes physiologiques et conséquences des calcifications cardiovasculaires: rôle des remodelages cardiovasculaires et osseux, Université de Picardie Jules Verne (UPJV)-Institut National de la Santé et de la Recherche Médicale (INSERM), HEMATIM - Hématopoïèse et immunologie - UR UPJV 4666 (HEMATIM), CHU Amiens-Picardie-Université de Picardie Jules Verne (UPJV)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neuro-Immunologie Virale - Viral Neuro-immunology, This work was funded by the Vaincre les Maladies Lysosomales (VML) charity., We thank Professor Elizabeth Neufeld for providing the MPSIIIB mice, and Dr. Bénédicte Heron (APHP, Hôpital Trousseau, Paris, France) for collecting urine samples from patients. We are grateful to Camille Rottier (CHU Amiens Picardie, Amiens, France), Dr. Julie Bruyère (Institut des Neurosciences, Grenoble) and Nathalie Dessendier (Centre Français des Porphyries ‐ Laboratoire de Biochimie, Hôpital Louis Mourier, Colombes, France) for excellent technical assistance. We thank the staff of ICAP plateform, Dr. Paulo Marcelo and Mrs. Luciane Zabijak, for assistance with confocal microscopy experiments (ICAP plateform, Université de Picardie Jules Verne, Amiens, France)., Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Mécanismes physiopathologiques et conséquences des calcifications vasculaires - UR UPJV 7517 (MP3CV), and Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie
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0301 basic medicine ,Sanfilippo syndrome ,MESH: Neurons ,microglia ,MESH: Mice, Knockout ,[SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology ,neuroinflammation ,MESH: Neurodegenerative Diseases ,Mucopolysaccharidosis III ,chemistry.chemical_compound ,iron ,0302 clinical medicine ,[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,MESH: Animals ,MESH: Mucopolysaccharidosis III ,Mice, Knockout ,Neurons ,MESH: Iron ,Microglia ,Brain ,Neurodegenerative Diseases ,[SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology ,Heparan sulfate ,[SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism ,MESH: Microglia ,medicine.anatomical_structure ,Neurology ,Cerebral cortex ,medicine.medical_specialty ,Mucopolysaccharidosis type III ,Biology ,MESH: Brain ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Hepcidin ,Internal medicine ,[SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO] ,medicine ,Animals ,Neuroinflammation ,[SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology ,medicine.disease ,MESH: Astrocytes ,030104 developmental biology ,Endocrinology ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,chemistry ,Astrocytes ,TLR4 ,biology.protein ,hepcidin ,030217 neurology & neurosurgery - Abstract
International audience; Neuroinflammation and iron accumulation are hallmarks of a variety of adult neurodegenerative diseases. In Sanfilippo syndrome (mucopolysaccharidosis type III, MPSIII, a pediatric neurodegenerative disease that shares some features with adult neurodegenerative diseases), the progressive accumulation of heparan sulfate oligosaccharides (HSOs) induces microglia and astrocytes to produce pro-inflammatory cytokines leading to severe neuroinflammation. The objectives of the present study were (1) to measure the local iron concentration and to assess iron metabolism in the brain of a MPSIIIB murine model and (2) to identify the brain cells involved in this accumulation. We found that iron accumulation in MPSIIIB mice primarily affected the cerebral cortex where hepcidin levels were higher than in wild-type mice, and increased with aging. This increase was correlated with low expression of ferroportin 1 (FPN1), and thus brain iron retention. Moreover, we showed in vitro that HSOs are directly responsible for the production of hepcidin and the relative decrease in FPN1 expression when added to cultures of microglia and, to a lesser extent, to cultures of astrocytes. In contrast, no significant differences were observed in neurons. Hepcidin induction results from activation of the TLR4 pathway and STAT3 signaling, and leads to iron retention within microglia. Our results show that microglia have a key role in cerebral hepcidin overexpression and thus in the brain iron accumulation observed in the MPSIIIB model.
- Published
- 2018