| Title: |
Decreased microglial Wnt/β-catenin signalling drives microglial pro-inflammatory activation in the developing brain |
| Authors: |
van Steenwinckel, Juliette; Schang, Anne-Laure; Krishnan, Michelle, L; Degos, Vincent; Delahaye-Duriez, Andrée; Bokobza, Cindy; Csaba, Zsolt; Verdonk, Franck; Montané, Amélie; Sigaut, Stéphanie; Hennebert, Olivier; Lebon, Sophie; Schwendimann, Leslie; Le Charpentier, Tifenn; Hassan-Abdi, Rahma; Ball, Gareth; Aljabar, Paul; Saxena, Alka; Holloway, Rebecca, K; Birchmeier, Walter; Baud, Olivier; Rowitch, David; Miron, Veronique; Chretien, Fabrice; Chrétien, Fabrice; Leconte, Claire; Besson, Valérie; Petretto, Enrico; Edwards, A. David; Hagberg, Henrik; Soussi-Yanicostas, Nadia; Fleiss, Bobbi; Gressens, Pierre |
| Contributors: |
Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)); Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité); PremUp Foundation; Institut de Recherche pour le Développement (IRD)-CHI Créteil-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris-Saclay-Université Paris Cité (UPCité); Laboratoire de Chimie et Toxicologie Analytique et Cellulaire (EA 4463); Université Paris Descartes - Paris 5 (UPD5); King‘s College London; CHU Pitié-Salpêtrière AP-HP; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU); UFR Santé, Médecine et Biologie Humaine (UFR SMBH); Université Sorbonne Paris Nord; Sorbonne Université - Faculté de Médecine (SU FM); Sorbonne Université (SU); Histopathologie humaine et Modèles animaux; Institut Pasteur Paris (IP); Conservatoire National des Arts et Métiers Cnam (Cnam); NIHR Biomedical Research Centre London; King‘s College London-Guy's and St Thomas' NHS Foundation Trust; Queen's Medical Researche Institute; The University of Edinburgh; Max Delbrueck Center for Molecular Medicine; Helmholtz-Gemeinschaft = Helmholtz Association; University of Cambridge Cambridge, UK (CAM); Centre Hospitalier Sainte Anne Paris; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP); Pharmacologie de la circulation cérébrale (EA 4475); Duke-NUS Medical School Singapore; Göteborgs Universitet = University of Gothenburg (GU); Royal Melbourne Institute of Technology University (RMIT University); This study was supported by grants from Inserm, Université Paris Diderot, Université Sorbonne-Paris-Cité, Investissement d'Avenir (ANR-11-INBS-0011, NeurATRIS), ERA-NET Neuron (Micromet), DHU PROTECT, Association Robert Debré, PremUP, Fondation de France, Fondation pour la Recherche sur le Cerveau, Fondation des Gueules Cassées, Roger de Spoelberch Foundation, Grace de Monaco Foundation, Leducq Foundation, Action Medical Research, Cerebral Palsy Alliance Research Foundation Australia, Wellcome Trust (WSCR P32674) and The Swedish Research Council (2015-02493). We wish to acknowledge the support of the Department of Perinatal Imaging and Health, King’s College London. In addition, the authors acknowledge financial support from the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.; ANR-11-INBS-0011,NeurATRIS,Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences(2011) |
| Source: |
ISSN: 0006-8950. |
| Publisher Information: |
CCSD; Oxford University Press |
| Publication Year: |
2019 |
| Collection: |
Université Paris 13: HAL |
| Subject Terms: |
neonatal encephalopathy; innate immunity; neuroinflammation; neuroprotection; 3DNA; [SDV]Life Sciences [q-bio]; [SCCO]Cognitive science; [SCCO.NEUR]Cognitive science/Neuroscience; [SDV.BBM]Life Sciences [q-bio]/Biochemistry; Molecular Biology; [SDV.BDD]Life Sciences [q-bio]/Development Biology; [SDV.IMM]Life Sciences [q-bio]/Immunology |
| Description: |
International audience ; Microglia of the developing brain have unique functional properties but how their activation states are regulated is poorly understood. Inflammatory activation of microglia in the still-developing brain of preterm-born infants is associated with permanent neurological sequelae in 9 million infants every year. Investigating the regulators of microglial activation in the developing brain across models of neuroinflammation-mediated injury (mouse, zebrafish) and primary human and mouse microglia we found using analysis of genes and proteins that a reduction in Wnt/b-catenin signalling is necessary and sufficient to drive a microglial phenotype causing hypomyelination. We validated in a cohort of preterm-born infants that genomic variation in the Wnt pathway is associated with the levels of connectivity found in their brains. Using a Wnt agonist delivered by a blood-brain barrier penetrant microglia-specific targeting nanocarrier we prevented in our animal model the pro-inflammatory microglial activation, white matter injury and behavioural deficits. Collectively, these data validate that the Wnt pathway regulates microglial activation, is critical in the evolution of an important form of human brain injury and is a viable therapeutic target. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
info:eu-repo/semantics/altIdentifier/pmid/31665242; PUBMED: 31665242; PUBMEDCENTRAL: PMC6906599 |
| DOI: |
10.1093/brain/awz319 |
| Availability: |
https://hal.science/hal-02357196; https://hal.science/hal-02357196v1/document; https://hal.science/hal-02357196v1/file/Regulation%20of%20microglial%20activation%20by%20Wnt_Van%20Steenwinckel.PDF%20.pdf; https://doi.org/10.1093/brain/awz319 |
| Rights: |
https://about.hal.science/hal-authorisation-v1/ ; info:eu-repo/semantics/OpenAccess |
| Accession Number: |
edsbas.6AD0B001 |
| Database: |
BASE |