Microglial inflammasome activation drives developmental white matter injury
| Autor: | Julie-Clare Becher, Colin Smith, Gemma Sullivan, Rebecca K. Holloway, Veronique E. Miron, James P. Boardman, Pierre Gressens, Graeme Ireland |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Follistatin Inflammasomes microglia Inflammation Endogeny Biology Mice 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Cerebrospinal fluid NLR Family Pyrin Domain-Containing 3 Protein medicine Animals Research Articles Microglia White Matter Injury myelination Inflammasome White Matter Oligodendrocyte Activins Disease Models Animal 030104 developmental biology medicine.anatomical_structure Neurology inflammation Brain Injuries white matter injury biology.protein medicine.symptom Neuroscience oligodendrocyte 030217 neurology & neurosurgery Research Article medicine.drug |
| Zdroj: | Glia |
| ISSN: | 1098-1136 0894-1491 |
| DOI: | 10.1002/glia.23963 |
| Popis: | 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. Main points Microglia inflammasome activation correlates with white matter injury.Inflammasome inhibition promotes myelination.IL1β increases the activin‐A inhibitor follistatin, which impedes myelination.Activin‐A enhances myelination following injury. |
| Databáze: | OpenAIRE |
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