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Updated: Jul 24, 2026
Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
Published on: January 30, 2014
Microglial inflammasome activation drives developmental white matter injury
Rebecca K Holloway1, Graeme Ireland1, Gemma Sullivan1
1Medical Research Council Centre for Reproductive Health, The Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, UK.
Abstract:
Injury to the developing brain during the perinatal period often causes hypomyelination, leading to clinical deficits for which there is an unmet therapeutic need. Dysregulation of inflammation and microglia have been implicated, yet the molecular mechanisms linking these to hypomyelination are unclear. Using human infant cerebrospinal fluid (CSF) and postmortem tissue, we found that microglial activation of the pro-inflammatory molecular complex the NLRP3 inflammasome is associated with pathology. By developing a novel mouse brain explant model of microglial inflammasome activation, we demonstrate that blocking the inflammasome rescues myelination. In human and mouse, we discovered a link between the inflammasome product IL1β and increased levels of follistatin, an endogenous inhibitor of activin-A. Follistatin treatment was sufficient to reduce myelination, whereas myelination was rescued in injured explants upon follistatin neutralization or supplementation with exogenous activin-A. Our data reveal that inflammasome activation in microglia drives hypomyelination and identifies novel therapeutic strategies to reinstate myelination following developmental injury.
Insights
Inflammasome activation in microglia causes hypomyelination in developing brains. Blocking this inflammasome pathway and targeting follistatin or activin-A shows promise for restoring myelination after injury.
Area of Science:
- Neuroscience
- Developmental Biology
- Immunology
Background:
- Perinatal brain injury frequently results in hypomyelination, causing significant clinical deficits.
- The precise molecular links between neuroinflammation, microglial activation, and hypomyelination remain incompletely understood.
- Existing therapeutic options for developmental brain injury-induced hypomyelination are limited.
Purpose of the Study:
- To elucidate the molecular mechanisms by which microglial inflammasome activation contributes to hypomyelination.
- To identify novel therapeutic targets for restoring myelination following perinatal brain injury.
- To investigate the role of the follistatin-activin-A axis in inflammasome-mediated hypomyelination.
Main Methods:
- Analysis of human infant cerebrospinal fluid (CSF) and postmortem brain tissue to assess microglial inflammasome activation and associated pathology.
- Development of a novel mouse brain explant model to study microglial inflammasome activation and its impact on myelination.
- Pharmacological manipulation of the NLRP3 inflammasome pathway and the follistatin-activin-A axis in both human and mouse models.
Main Results:
- Microglial activation of the NLRP3 inflammasome in human infant CSF and tissue correlates with neuropathology.
- Inhibition of the NLRP3 inflammasome in mouse brain explants successfully rescued myelination.
- A novel link was established between inflammasome product IL-1β, elevated follistatin levels, and reduced myelination.
- Follistatin administration impaired myelination, while its neutralization or activin-A supplementation restored myelination in injured explants.
Conclusions:
- NLRP3 inflammasome activation in microglia is a key driver of hypomyelination following perinatal brain injury.
- The follistatin-activin-A pathway is a critical mediator of inflammasome-induced hypomyelination.
- Targeting microglial inflammasomes and the follistatin-activin-A axis offers promising therapeutic strategies for treating developmental brain injury-related hypomyelination.
