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Updated: Oct 14, 2025
Characterization and Isolation of Mouse Primary Microglia by Density Gradient Centrifugation
Published on: February 16, 2018
miR-146b Protects the Perinatal Brain against Microglia-Induced Hypomyelination
Cindy Bokobza1, Pooja Joshi1, Anne-Laure Schang2
1Université de Paris, NeuroDiderot, Inserm, Paris, France.
Objectives:
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.
Methods:
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.
Results:
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.
Interpretations:
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.
Insights
MicroRNA-146b-5p regulates microglia activation, offering a potential therapeutic target to prevent brain injury in premature newborns. Enhancing its levels protected against white matter injury and cognitive deficits in a mouse model.
Area of Science:
- Neuroscience
- Immunology
- Developmental Biology
Background:
- Perinatal inflammation in premature infants triggers microglial activation, leading to neurodevelopmental injuries like white matter injury (WMI).
- Understanding the immune regulators of microglial activation is critical for developing interventions against WMI.
Purpose of the Study:
- To investigate the role of microRNA-146b-5p in microglial activation and its potential as a therapeutic target for perinatal brain injury.
- To elucidate the mechanism by which microRNA-146b-5p modulates microglial phenotype in the context of WMI.
Main Methods:
- Utilized ex vivo microglial cultures and a mouse model of WMI induced by perinatal inflammation (IL-1β).
- Analyzed microglial miRNome to identify candidate microRNAs; employed 3DNA nanocarriers for targeted delivery of synthetic miRNA-146b-5p to microglia.
- Assessed microglial activation, hypomyelination, and cognitive function in response to treatment.
Main Results:
- Reduced Dicer in microglia attenuated pro-inflammatory activation and prevented hypomyelination in the WMI model.
- MicroRNA-146b-5p was identified as a key modulator, overexpressed in LPS-stimulated microglia but reduced in extracellular vesicles (EVs).
- Targeted delivery of miRNA-146b-5p via 3DNA nanocarriers suppressed LPS-induced microglial activation, downregulated IRAK1, and restored EV levels, preventing WMI and cognitive defects.
Conclusions:
- MicroRNA-146b-5p acts as a significant regulator of microglial phenotype.
- Targeting miRNA-146b-5p holds promise for reducing the incidence and severity of perinatal brain injuries and their long-term consequences.
