title: USP18 lack in microglia causes destructive interferonopathy of the mouse brain.
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.
authors.affiliation: Institute of Neuropathology, University of Freiburg, Freiburg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Goldmann
authors.affiliation: Institute of Neuropathology, University of Freiburg, Freiburg, Germany.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Zeller
authors.affiliation: Institute of Neuropathology, University of Freiburg, Freiburg, Germany.
authors.forename: Jenni
authors.initials: J
authors.lastname: Raasch
authors.affiliation: Institute of Neuropathology, University of Freiburg, Freiburg, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Kierdorf
authors.affiliation: Institute of Neuropathology, University of Freiburg, Freiburg, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Frenzel
authors.affiliation: Institute of Neuropathology, University of Freiburg, Freiburg, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Ketscher
authors.affiliation: Institute of Neuropathology, University of Freiburg, Freiburg, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Basters
authors.affiliation: Institute of Neuropathology, University of Freiburg, Freiburg, Germany.
authors.forename: Ori
authors.initials: O
authors.lastname: Staszewski
authors.affiliation: Institute of Neuropathology, University of Freiburg, Freiburg, Germany.
authors.forename: Stefanie M
authors.initials: SM
authors.lastname: Brendecke
authors.affiliation: Institute of Neuropathology, University of Freiburg, Freiburg, Germany.
authors.forename: Alena
authors.initials: A
authors.lastname: Spiess
authors.affiliation: Institute of Neuropathology, University of Freiburg, Freiburg, Germany.
authors.forename: Tuan Leng
authors.initials: TL
authors.lastname: Tay
authors.affiliation: Institute of Physics & Center for Systems Biology (ZBSA), University of Freiburg, Freiburg, Germany.
authors.forename: Clemens
authors.initials: C
authors.lastname: Kreutz
authors.affiliation: Institute of Physics & Center for Systems Biology (ZBSA), University of Freiburg, Freiburg, Germany BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Timmer
authors.affiliation: Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Grazia M S
authors.initials: GM
authors.lastname: Mancini
authors.affiliation: Institute of Neuropathology, University of Freiburg, Freiburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Blank
authors.affiliation: Institute of Neuropathology, University of Freiburg, Freiburg, Germany.
authors.forename: Günter
authors.initials: G
authors.lastname: Fritz
authors.affiliation: Department of Psychiatry, University of Freiburg, Freiburg, Germany Department of Neuroscience, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Knut
authors.initials: K
authors.lastname: Biber
authors.affiliation: Institute of Clinical Microbiology, Immunology and Hygiene, University Hospital Erlangen, Erlangen, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Lang
authors.affiliation: Department of Human Genetics, McGill University, Montreal, QC, Canada.
authors.forename: Danielle
authors.initials: D
authors.lastname: Malo
authors.affiliation: Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.
authors.forename: Doron
authors.initials: D
authors.lastname: Merkler
authors.affiliation: Institute of Virology, Technische Universität München/Helmholtz-Zentrum Munich, München, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Heikenwälder
authors.affiliation: Institute of Neuropathology, University of Freiburg, Freiburg, Germany.
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Knobeloch
authors.affiliation: Institute of Neuropathology, University of Freiburg, Freiburg, Germany BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany marco.prinz@uniklinik-freiburg.de.
authors.forename: Marco
authors.initials: M
authors.lastname: Prinz
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism*; D003001:Cloning, Molecular; D017931:DNA Primers / Q000235:genetics; D010450:Endopeptidases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D006652:Histological Techniques; D007372:Interferons / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D046228:Microarray Analysis; D017628:Microglia / Q000378:metabolism*; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D008959:Models, Neurological; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D018709:Statistics, Nonparametric; D043222:Ubiquitin Thiolesterase
chemical_list: D017931:DNA Primers; D007372:Interferons; D010450:Endopeptidases; C485560:USP18 protein, human; D043222:Ubiquitin Thiolesterase
keywords: EAE; Usp18; microglia; multiple sclerosis; type I interferon