miR-146b Protects the Perinatal Brain against Microglia-Induced Hypomyelination.
Journal
Annals of neurology
ISSN: 1531-8249
Titre abrégé: Ann Neurol
Pays: United States
ID NLM: 7707449
Informations de publication
Date de publication:
01 2022
01 2022
Historique:
revised:
03
11
2021
received:
07
05
2020
accepted:
03
11
2021
pubmed:
7
11
2021
medline:
15
1
2022
entrez:
6
11
2021
Statut:
ppublish
Résumé
In the premature newborn, perinatal inflammation mediated by microglia contributes significantly to neurodevelopmental injuries including white matter injury (WMI). Brain inflammation alters development through neuroinflammatory processes mediated by activation of homeostatic microglia toward a pro-inflammatory and neurotoxic phenotype. Investigating immune regulators of microglial activation is crucial to find effective strategies to prevent and treat WMI. Ex vivo microglial cultures and a mouse model of WMI induced by perinatal inflammation (interleukin-1-beta [IL-1β] and postnatal days 1-5) were used to uncover and elucidate the role of microRNA-146b-5p in microglial activation and WMI. A specific reduction in vivo in microglia of Dicer, a protein required for microRNAs maturation, reduces pro-inflammatory activation of microglia and prevents hypomyelination in our model of WMI. Microglial miRNome analysis in the WMI model identified miRNA-146b-5p as a candidate modulator of microglial activation. Ex vivo microglial cell culture treated with the pro-inflammatory stimulus lipopolysaccharide (LPS) led to overexpression of immunomodulatory miRNA-146b-5p but its drastic reduction in the microglial extracellular vesicles (EVs). To increase miRNA-146b-5p expression, we used a 3DNA nanocarrier to deliver synthetic miRNA-146b-5p specifically to microglia. Enhancing microglial miRNA-146b-5p overexpression significantly decreased LPS-induced activation, downregulated IRAK1, and restored miRNA-146b-5p levels in EVs. In our WMI model, 3DNA miRNA-146b-5p treatment significantly prevented microglial activation, hypomyelination, and cognitive defect induced by perinatal inflammation. These findings support that miRNA-146b-5p is a major regulator of microglia phenotype and could be targeted to reduce the incidence and the severity of perinatal brain injuries and their long-term consequences. ANN NEUROL 2022;91:48-65.
Identifiants
pubmed: 34741343
doi: 10.1002/ana.26263
pmc: PMC9298799
doi:
Substances chimiques
MicroRNAs
0
Mirn146 microRNA, mouse
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
48-65Subventions
Organisme : Agence Nationale de la Recherche
ID : Investissement d'Avenir -ANR-11-INBS-0011 NeurATRI
Organisme : ERANET NEURON
ID : TRAINS
Organisme : EUR G.E.N.E
ID : #ANR-17-EURE-0013
Organisme : Fondation de France
Organisme : Fondation des Gueules Cassees
Organisme : Fondation Grace de Monaco
Organisme : Fondation pour le Recherche Medicale
Organisme : Fondation Roger de Spoelberch
Organisme : Guy's & St Thomas' NHS Foundation Trust
Organisme : Horizon 2020 Framework Program of the European Union
ID : 874721/PREMSTEM
Organisme : Institut National de la Sante et de la Recherche Medicale
Organisme : Universite Paris Diderot
Informations de copyright
© 2021 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
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