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

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 BirchmeierOlivier 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

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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.

Original language	English
Pages (from-to)	3806–3833
Journal	Brain : a journal of neurology
Volume	142
Issue number	12
Early online date	30 Oct 2019
DOIs	https://doi.org/10.1093/brain/awz319
Publication status	Published - Dec 2019

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Decreased microglial Wnt:β-catenin signalling_VAN STEENWINCKEL_Accepted30Aug2019_ePublished30Oct2019_GREEN AAMAccepted author manuscript, 520 KB

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Van Steenwinckel, J., Schang, A.-L., Krishnan, M. L., Degos, V., Delahaye-Duriez, A., Bokobza, C., Csaba, Z., Verdonk, F., Montané, A., Sigaut, S., Hennebert, O., Lebon, S., Schwendimann, L., Le Charpentier, T., Hassan-Abdi, R., Ball, G., Aljabar, P., Saxena, A., Holloway, R. K., ... Gressens, P. (2019). Decreased microglial Wnt/β-catenin signalling drives microglial pro-inflammatory activation in the developing brain. Brain : a journal of neurology, 142(12), 3806–3833. https://doi.org/10.1093/brain/awz319

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

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.",

author = "{Van Steenwinckel}, Juliette and Anne-Laure Schang and Krishnan, {Michelle L} and Vincent Degos and Andr{\'e}e Delahaye-Duriez and Cindy Bokobza and Zsolt Csaba and Franck Verdonk and Am{\'e}lie Montan{\'e} and St{\'e}phanie Sigaut and Olivier Hennebert and Sophie Lebon and Leslie Schwendimann and {Le Charpentier}, Tifenn and Rahma Hassan-Abdi and Gareth Ball and Paul Aljabar and Alka Saxena and Holloway, {Rebecca K} and Walter Birchmeier and Olivier Baud and David Rowitch and Veronique Miron and Fabrice Chretien and Claire Leconte and Besson, {Val{\'e}rie C} and Petretto, {Enrico G} and Edwards, {A David} and Henrik Hagberg and Nadia Soussi-Yanicostas and Bobbi Fleiss and Pierre Gressens",

year = "2019",

month = dec,

doi = "10.1093/brain/awz319",

language = "English",

volume = "142",

pages = "3806–3833",

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Van Steenwinckel, J, Schang, A-L, Krishnan, ML, Degos, V, Delahaye-Duriez, A, Bokobza, C, Csaba, Z, Verdonk, F, Montané, A, Sigaut, S, Hennebert, O, Lebon, S, Schwendimann, L, Le Charpentier, T, Hassan-Abdi, R, Ball, G , Aljabar, P, Saxena, A, Holloway, RK, Birchmeier, W, Baud, O, Rowitch, D, Miron, V, Chretien, F, Leconte, C, Besson, VC, Petretto, EG, Edwards, AD , Hagberg, H, Soussi-Yanicostas, N, Fleiss, B & Gressens, P 2019, 'Decreased microglial Wnt/β-catenin signalling drives microglial pro-inflammatory activation in the developing brain', Brain : a journal of neurology, vol. 142, no. 12, pp. 3806–3833. https://doi.org/10.1093/brain/awz319

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T1 - Decreased microglial Wnt/β-catenin signalling drives microglial pro-inflammatory activation in the developing brain

AU - Van Steenwinckel, Juliette

AU - Schang, Anne-Laure

AU - Krishnan, Michelle L

AU - Degos, Vincent

AU - Delahaye-Duriez, Andrée

AU - Bokobza, Cindy

AU - Csaba, Zsolt

AU - Verdonk, Franck

AU - Montané, Amélie

AU - Sigaut, Stéphanie

AU - Hennebert, Olivier

AU - Lebon, Sophie

AU - Schwendimann, Leslie

AU - Le Charpentier, Tifenn

AU - Hassan-Abdi, Rahma

AU - Ball, Gareth

AU - Aljabar, Paul

AU - Saxena, Alka

AU - Holloway, Rebecca K

AU - Birchmeier, Walter

AU - Baud, Olivier

AU - Rowitch, David

AU - Miron, Veronique

AU - Chretien, Fabrice

AU - Leconte, Claire

AU - Besson, Valérie C

AU - Petretto, Enrico G

AU - Edwards, A David

AU - Hagberg, Henrik

AU - Soussi-Yanicostas, Nadia

AU - Fleiss, Bobbi

AU - Gressens, Pierre

PY - 2019/12

Y1 - 2019/12

N2 - 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.

AB - 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.

U2 - 10.1093/brain/awz319

DO - 10.1093/brain/awz319

M3 - Article

C2 - 31665242

SN - 0006-8950

VL - 142

SP - 3806

EP - 3833

JO - Brain : a journal of neurology

JF - Brain : a journal of neurology

IS - 12

ER -

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

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