Die Gewebe-spezifische Rolle von UBP43 für die Homöostase des Gehirns und bei autoimmunen Entzündungen des Zentralnervensystems
Final Report Abstract
Microglia are tissue macrophages of the central nervous system (CNS) that control tissue homeostasis, and as such they are crucially important for organ integrity. 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. By using expression studies, we identified the ubiquitin-specific protease (Usp) 18 in white matter microglia that essentially contributes to microglial quiescence under homeostatic conditions. We further found that microglial Usp18 negatively regulates the activation of STAT1 and concomitant induction of interferon-induced genes thereby disabling the termination of IFN signaling. The Usp18-mediated control was independent from the catalytic activity of the protease but instead required the interaction with Ifnar2. Additionally, the absence of Ifnar1 completely restored microglial activation indicating a tonic IFN signal which needs to be negatively controlled by USP18 under non-diseased conditions. Finally, conditional depletion of Usp18 only in myeloid cells significantly enhanced the disease burden in a mouse model of CNS autoimmunity, increased axonal damage and determined the spatial distribution of CNS lesions that shared the same STAT1 signature as myeloid cells found in active multiple sclerosis (MS) lesions. These results identify Usp18 as a novel and critical negative regulator of microglia activation, demonstrate a protective role of USP18 for microglia function by regulating the IFNAR pathway, and establish Usp18 as a potential therapeutic target for the treatment of MS.
Publications
-
USP18 lack in microglia causes destructive interferonopathy of the mouse brain. The EMBO Journal (2015) e201490791
Goldmann T, Zeller N, Raasch J, Kierdorf K, Frenzel K, Ketscher K, Basters A, Staszewski O, Brendecke SM, Spieß A, Tay TL, Kreutz C, Timmer J, Grazia MS Mancini, Blank T, Fritz G, Biber K, Lang R, Malo D, Merkler D, Heikenwälder M, Knobeloch KP, Prinz M
