@article{1dadbed83b734ebe80827e46d8a323a6,
title = "Microglial inflammasome activation drives developmental white matter injury",
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.",
keywords = "inflammation, microglia, myelination, oligodendrocyte, white matter injury",
author = "Holloway, {Rebecca K.} and Graeme Ireland and Gemma Sullivan and Becher, {Julie Clare} and Colin Smith and Boardman, {James P.} and Pierre Gressens and Miron, {Veronique E.}",
note = "Funding Information: The authors thank the Medical Research Council Brain Bank, INSERM-Universit? Paris Diderot, and David Rowitch and Stephen Fancy from the Newborn Brain Research Institute (UCSF) for providing human postmortem tissue. The authors also thank Rozalia Pataky, Sharan Mahtani, Bobbi Fleiss, Patricia Nimmo, Karina McDade, and Hui-Hsin Tsai for technical support. This project was supported by Action Medical Research/The Rooney Foundation via the Kent Community Foundation (V.E.M., P.G; GN2318), Tommy's the Baby Charity (V.E.M.), a Medical Research Council Career Development Award (V.E.M.; MR/M020827/1), and funds from the Medical Research Council Centre for Reproductive Health (MR/N02256/1). Diagrams were created using BioRender.com. Funding Information: The authors thank the Medical Research Council Brain Bank, INSERM‐Universit{\'e} Paris Diderot, and David Rowitch and Stephen Fancy from the Newborn Brain Research Institute (UCSF) for providing human postmortem tissue. The authors also thank Rozalia Pataky, Sharan Mahtani, Bobbi Fleiss, Patricia Nimmo, Karina McDade, and Hui‐Hsin Tsai for technical support. This project was supported by Action Medical Research/The Rooney Foundation via the Kent Community Foundation (V.E.M., P.G; GN2318), Tommy's the Baby Charity (V.E.M.), a Medical Research Council Career Development Award (V.E.M.; MR/M020827/1), and funds from the Medical Research Council Centre for Reproductive Health (MR/N02256/1). Diagrams were created using BioRender.com . Publisher Copyright: {\textcopyright} 2021 The Authors. Glia published by Wiley Periodicals LLC. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",
year = "2021",
month = may,
doi = "10.1002/glia.23963",
language = "English",
volume = "69",
pages = "1268--1280",
journal = "GLIA",
issn = "0894-1491",
publisher = "Wiley",
number = "5",
}