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Activated microglia drive demyelination via CSF1R signaling.

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.

SUBMITTER: Marzan DE

PROVIDER: S-EPMC9250806 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Severe demyelinating disorders of the central nervous system (CNS) such as multiple sclerosis (MS), can be devastating for many young lives. To date, the factors resulting in poor remyelination and repair are not well understood, and reparative therapies that benefit MS patients have yet to be developed. We have previously shown that the activity and abundance of Lipoprotein Lipase (LPL)-the rate-limiting enzyme in the hydrolysis of triglyceride-rich lipoproteins-is increased in Schwann cells and macrophages following nerve crush injury in the peripheral nervous system (PNS), suggesting that LPL may help scavenge myelin-derived lipids. We hypothesized that LPL may play a similar role in the CNS. To test this, mice were immunized with MOG35-55 peptide to induce experimental allergic encephalomyelitis (EAE). LPL activity was increased (p < 0.05) in the brain at 30 days post-injection, coinciding with partial remission of clinical symptoms. Furthermore, LPL abundance and activity was up-regulated (p < 0.05) at the transition between de- and re-myelination in lysolecithin-treated ex vivo cerebellar slices. Since microglia are the key immune effector cells of the CNS we determined the role of LPL in microglia. Lipid uptake was decreased (p < 0.001) in LPL-deficient BV-2 microglial cells compared to WT. In addition, LPL-deficient cells showed dramatically reduced expression of anti-inflammatory markers, YM1 (-22 fold, p < 0.001), and arginase 1 (Arg1; -265 fold, p < 0.001) and increased expression of pro-inflammatory markers, such as iNOS compared to WT cells (+53 fold, p < 0.001). This suggests that LPL is a feature of reparative microglia, further supported by the metabolic and inflammatory profile of LPL-deficient microglia. Taken together, our data strongly suggest that LPL expression is a novel feature of a microglial phenotype that supports remyelination and repair through the clearance of lipid debris. This mechanism may be exploited to develop future reparative therapies for MS and primary neurodegenerative disorders (Alzheimer's disease (AD) and Parkinson's disease).

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Activated microglia drive demyelination via CSF1R signaling.

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