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Characterization and Isolation of Mouse Primary Microglia by Density Gradient Centrifugation
Published on: February 16, 2018
USP18 lack in microglia causes destructive interferonopathy of the mouse brain
Tobias Goldmann1, Nicolas Zeller1, Jenni Raasch1
1Institute of Neuropathology, University of Freiburg, Freiburg, Germany.
Abstract:
Microglia are tissue macrophages of the central nervous system (CNS) that control tissue homeostasis. Microglia dysregulation is thought to be causal for a group of neuropsychiatric, neurodegenerative and neuroinflammatory diseases, called "microgliopathies". However, how the intracellular stimulation machinery in microglia is controlled is poorly understood. Here, we identified the ubiquitin-specific protease (Usp) 18 in white matter microglia that essentially contributes to microglial quiescence. We further found that microglial Usp18 negatively regulates the activation of Stat1 and concomitant induction of interferon-induced genes, thereby terminating IFN signaling. The Usp18-mediated control was independent from its catalytic activity but instead required the interaction with Ifnar2. Additionally, the absence of Ifnar1 restored microglial activation, indicating a tonic IFN signal which needs to be negatively controlled by Usp18 under non-diseased conditions. These results identify Usp18 as a critical negative regulator of microglia activation and demonstrate a protective role of Usp18 for microglia function by regulating the Ifnar pathway. The findings establish Usp18 as a new molecule preventing destructive microgliopathy.
Insights
Ubiquitin-specific protease (Usp) 18 maintains quiescent microglia by regulating Stat1 and interferon signaling. This discovery reveals Usp18 as a key molecule preventing microgliopathies and protecting microglial function.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglia, the resident immune cells of the central nervous system (CNS), are crucial for maintaining tissue homeostasis.
- Dysregulation of microglia is implicated in various neurological disorders, termed microgliopathies.
- The intracellular mechanisms controlling microglial activation remain incompletely understood.
Purpose of the Study:
- To investigate the role of ubiquitin-specific protease (Usp) 18 in regulating microglial function.
- To elucidate the molecular mechanisms by which Usp18 controls microglial activation and interferon signaling.
Main Methods:
- Identification of Usp18 in white matter microglia.
- Analysis of Usp18's effect on Stat1 activation and interferon-induced gene expression.
- Investigation of Usp18's interaction with Ifnar2 and the functional consequences of Ifnar1 absence.
Main Results:
- Usp18 was identified as a key contributor to microglial quiescence.
- Microglial Usp18 negatively regulates Stat1 activation and interferon signaling by interacting with Ifnar2.
- Absence of Ifnar1 restored microglial activation, suggesting a tonic interferon signal regulated by Usp18.
Conclusions:
- Usp18 acts as a critical negative regulator of microglia activation.
- Usp18 plays a protective role in microglial function by modulating the interferon (IFN) pathway.
- Usp18 is identified as a novel therapeutic target for preventing destructive microgliopathies.
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