Decreased microglial Wnt/β-catenin signalling drives microglial pro-inflammatory activation in the developing brain

Juliette Van Steenwinckel; Anne-Laure Schang; Michelle L Krishnan; Vincent Degos; Andrée Delahaye-Duriez; Cindy Bokobza; Zsolt Csaba; Franck Verdonk; Amélie Montané; Stéphanie Sigaut; Olivier Hennebert; Sophie Lebon; Leslie Schwendimann; Tifenn Le Charpentier; Rahma Hassan-Abdi; Gareth Ball; Paul Aljabar; Alka Saxena; Rebecca K Holloway; Walter Birchmeier; Olivier Baud; David Rowitch; Veronique Miron; Fabrice Chretien; Claire Leconte; Valérie C Besson; Enrico G Petretto; A David Edwards; Henrik Hagberg; Nadia Soussi-Yanicostas; Bobbi Fleiss; Pierre Gressens

doi:10.1093/brain/awz319

Decreased microglial Wnt/β-catenin signalling drives microglial pro-inflammatory activation in the developing brain

Brain. 2019 Dec 1;142(12):3806-3833. doi: 10.1093/brain/awz319.

Authors

Juliette Van Steenwinckel^{1

2}, Anne-Laure Schang^{1

2

3}, Michelle L Krishnan⁴, Vincent Degos^{1

2

5}, Andrée Delahaye-Duriez^{1

6}, Cindy Bokobza^{1

2}, Zsolt Csaba^{1

2}, Franck Verdonk^{7

8}, Amélie Montané^{1

2}, Stéphanie Sigaut^{1

2}, Olivier Hennebert^{1

2

9}, Sophie Lebon^{1

2}, Leslie Schwendimann^{1

2}, Tifenn Le Charpentier^{1

2}, Rahma Hassan-Abdi^{1

2}, Gareth Ball⁴, Paul Aljabar⁴, Alka Saxena¹⁰, Rebecca K Holloway¹¹, Walter Birchmeier¹², Olivier Baud^{1

2}, David Rowitch¹³, Veronique Miron¹¹, Fabrice Chretien^{6

7

14}, Claire Leconte¹⁵, Valérie C Besson¹⁵, Enrico G Petretto¹⁶, A David Edwards⁴, Henrik Hagberg^{4

17}, Nadia Soussi-Yanicostas^{1

2}, Bobbi Fleiss^{1

2

4

18}, Pierre Gressens^{1

2

4}

Affiliations

¹ Université de Paris, NeuroDiderot, Inserm, F-75019 Paris, France.
² PremUP, F-75006 Paris, France.
³ UMR CNRS 8638-Chimie Toxicologie Analytique et Cellulaire, Université Paris Descartes, Sorbonne Paris Cité, Faculté de Pharmacie de Paris, 4 Avenue de l'Observatoire, F-75006 Paris, France.
⁴ Centre for the Developing Brain, Division of Imaging Sciences and Biomedical Engineering, King's College London, King's Health Partners, St. Thomas' Hospital, London, SE1 7EH, UK.
⁵ Department of Anesthesia and Intensive Care, Pitié Salpétrière Hospital, F-75013 Paris France.
⁶ UFR de Santé, Médecine et Biologie Humaine, Université Paris 13, Sorbonne Paris Cité, F-93000 Bobigny, France.
⁷ Infection and Epidemiology Department, Human Histopathology and Animal Models Unit, Institut Pasteur, F-75015 Paris, France.
⁸ Paris Descartes University, Sorbonne Paris Cité, F-75006 Paris, France.
⁹ Conservatoire national des arts et métiers, F-75003 Paris, France.
¹⁰ Genomics Core Facility, NIHR Biomedical Research Centre, Guy's and St Thomas' NHS Foundation Trust, London, SE1 9RT, UK.
¹¹ MRC Centre for Reproductive Health, The Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, EH16 4TJ, UK.
¹² Cancer Research Program, Max Delbrueck Center for Molecular Medicine in the Helmholtz Society, Berlin-Buch, Germany.
¹³ Department of Paediatrics, University of Cambridge, Cambridge, CB2 0QQ, UK.
¹⁴ Laboratoire de Neuropathologie, Centre Hospitalier Sainte Anne, F-75014 Paris, France.
¹⁵ EA4475 - Pharmacologie de la Circulation Cérébrale, Faculté de Pharmacie de Paris, Université Paris Descartes, Sorbonne Paris Cité, F-75006 Paris, France.
¹⁶ Duke-NUS Medical School, 8 College Road 169857, Singapore.
¹⁷ Perinatal Center, Institute of Clinical Sciences and Institute of Neuroscience and Physiology, Sahlgrenska Academy, Gothenburg University, 41390 Gothenburg, Sweden.
¹⁸ School of Health and Biomedical Sciences, RMIT University, Bundoora, 3083, VIC, Australia.

Abstract

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/β-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.

Keywords: 3DNA; innate immunity; neonatal encephalopathy; neuroinflammation; neuroprotection.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Animals, Genetically Modified
Blood-Brain Barrier / metabolism
Brain / metabolism*
Cells, Cultured
Computational Biology
Humans
Inflammation / metabolism*
Mice
Microglia / metabolism*
Wnt Signaling Pathway / physiology*
Zebrafish

Abstract

Publication types

MeSH terms

Grants and funding