USP18 lack in microglia causes destructive interferonopathy of the mouse brain

• Published in: The EMBO journal Vol. 34; no. 12; pp. 1612 - 1629
• Main Authors: Goldmann, Tobias, Zeller, Nicolas, Raasch, Jenni, Kierdorf, Katrin, Frenzel, Kathrin, Ketscher, Lars, Basters, Anja, Staszewski, Ori, Brendecke, Stefanie M, Spiess, Alena, Tay, Tuan Leng, Kreutz, Clemens, Timmer, Jens, Mancini, Grazia MS, Blank, Thomas, Fritz, Günter, Biber, Knut, Lang, Roland, Malo, Danielle, Merkler, Doron, Heikenwälder, Mathias, Knobeloch, Klaus-Peter, Prinz, Marco
• Format: Journal Article
• Language: English
• Published: London Blackwell Publishing Ltd 12-06-2015; Nature Publishing Group UK; BlackWell Publishing Ltd
• Subjects: Animals; Blotting, Western; Brain; Brain - metabolism; Central nervous system; Cloning, Molecular; DNA Primers - genetics; EAE; EMBO19; EMBO27; Endopeptidases - deficiency; Endopeptidases - genetics; Endopeptidases - metabolism; Histological Techniques; Immune system; Interferons - metabolism; Mice; Mice, Knockout; Microarray Analysis; microglia; Microglia - metabolism; Microscopy, Electron, Transmission; Microscopy, Fluorescence; Models, Neurological; multiple sclerosis; Neurology; Proteases; Real-Time Polymerase Chain Reaction; Rodents; Signal Transduction - genetics; Signal Transduction - physiology; Statistics, Nonparametric; type I interferon; Usp18; type I interferon; EAE; Usp18; microglia; multiple sclerosis
• ISSN: 0261-4189; 1460-2075
• DOI: 10.15252/embj.201490791

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.
Synopsis
This study identifies Usp18 as a new critical negative regulator of microglia activation and demonstrates a protective role of Usp18 for microglia function by regulating IFN signaling.
The protease USP18 is expressed in white matter microglia.
Loss of USP18 induces white matter microglia activation and leads to microgliopathy.
Microglia activation in the absence of USP18 is due to prolonged STAT1 phosphorylation.
Constitutive IFN type I signaling in microglia during steady state.
The Ifnar2 interaction domain rather then the protease function of USP19 controls microglia activation.
Graphical Abstract
The non‐catalytic anti‐inflammatory function of a deubiquitination enzyme plays a key role in preventing microglia activation and neuroinflammation in mouse brains.