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• W3132955229 endingPage "1604" @default.
• W3132955229 startingPage "1583" @default.
• W3132955229 abstract "Microgliosis is a prominent pathological feature in many neurological diseases including multiple sclerosis (MS), a progressive auto-immune demyelinating disorder. The precise role of microglia, parenchymal central nervous system (CNS) macrophages, during demyelination, and the relative contributions of peripheral macrophages are incompletely understood. Classical markers used to identify microglia do not reliably discriminate between microglia and peripheral macrophages, confounding analyses. Here, we use a genetic fate mapping strategy to identify microglia as predominant responders and key effectors of demyelination in the cuprizone (CUP) model. Colony-stimulating factor 1 (CSF1), also known as macrophage colony-stimulating factor (M-CSF) - a secreted cytokine that regulates microglia development and survival-is upregulated in demyelinated white matter lesions. Depletion of microglia with the CSF1R inhibitor PLX3397 greatly abrogates the demyelination, loss of oligodendrocytes, and reactive astrocytosis that results from CUP treatment. Electron microscopy (EM) and serial block face imaging show myelin sheaths remain intact in CUP treated mice depleted of microglia. However, these CUP-damaged myelin sheaths are lost and robustly phagocytosed upon-repopulation of microglia. Direct injection of CSF1 into CNS white matter induces focal microgliosis and demyelination indicating active CSF1 signaling can promote demyelination. Finally, mice defective in adopting a toxic astrocyte phenotype that is driven by microglia nevertheless demyelinate normally upon CUP treatment implicating microglia rather than astrocytes as the primary drivers of CUP-mediated demyelination. Together, these studies indicate activated microglia are required for and can drive demyelination directly and implicate CSF1 signaling in these events." @default.
• W3132955229 created "2021-03-01" @default.
• W3132955229 creator A5000746001 @default.
• W3132955229 creator A5044110566 @default.
• W3132955229 creator A5062858244 @default.
• W3132955229 creator A5082808793 @default.
• W3132955229 creator A5085858912 @default.
• W3132955229 creator A5091277884 @default.
• W3132955229 date "2021-02-23" @default.
• W3132955229 modified "2023-10-14" @default.
• W3132955229 title "Activated microglia drive demyelination via <scp>CSF1R</scp> signaling" @default.
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