Cited by 237Neuroinflammation and Neurodegeneration Mechanismsinterferon and immune responsesUbiquitin and proteasome pathways

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USP18 lack in microglia causes destructive interferonopathy of the mouse brain

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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·2015·The EMBO Journal

DOI 10.15252/embj.201490791PMC PMC4475397

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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.

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Additional file 7 of Minocycline protects against microgliopathy in a Csf1r haplo-insufficient mouse model of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP)
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Additional file 2 of Minocycline protects against microgliopathy in a Csf1r haplo-insufficient mouse model of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP)
Li, X., Hu, B., Xiaoyan, G., Wang, Z., Zhou, Y., Sun, H., Zhang, X., Li, Y., Huang, X., Zhao, Y., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26593163
Additional file 1 of Single cell analysis reveals the roles and regulatory mechanisms of type-I interferons in Parkinson’s disease
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Additional file 8 of Microglial responses to CSF1 overexpression do not promote the expansion of other glial lineages
De, I., Maklakova, V. I., Litscher, S. J., Boyd, M. M., Klemm, L. C., Wang, Z., Kendziorski, C. M., & Collier, L. S. (2021) · Figshare · doi:10.6084/m9.figshare.15020549
Additional file 5 of Microglial responses to CSF1 overexpression do not promote the expansion of other glial lineages
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Additional file 3 of Minocycline protects against microgliopathy in a Csf1r haplo-insufficient mouse model of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP)
Li, X., Hu, B., Xiaoyan, G., Wang, Z., Zhou, Y., Sun, H., Zhang, X., Li, Y., Huang, X., Zhao, Y., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26593166
Additional file 9 of Microglial responses to CSF1 overexpression do not promote the expansion of other glial lineages
De, I., Maklakova, V. I., Litscher, S. J., Boyd, M. M., Klemm, L. C., Wang, Z., Kendziorski, C. M., & Collier, L. S. (2021) · Figshare · doi:10.6084/m9.figshare.15020552
Additional file 3 of Single cell analysis reveals the roles and regulatory mechanisms of type-I interferons in Parkinson’s disease
Quan, P., Li, X., Si, Y., Sun, L., Ding, F. F., Fan, Y., Liu, H., Wei, C., Li, R., Zhao, X. L., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26701096
Additional file 1 of Minocycline protects against microgliopathy in a Csf1r haplo-insufficient mouse model of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP)
Li, X., Hu, B., Xiaoyan, G., Wang, Z., Zhou, Y., Sun, H., Zhang, X., Li, Y., Huang, X., Zhao, Y., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26593160
Additional file 3 of Microglial senescence contributes to female-biased neuroinflammation in the aging mouse hippocampus: implications for Alzheimer’s disease
Ocañas, S. R., Pham, K. D., Cox, J. E. J., Keck, A. W., Ko, S., Ampadu, F. A., Porter, H. L., Ansere, V. A., Kulpa, A. M., Kellogg, C. M., et al. (2023) · Figshare · doi:10.6084/m9.figshare.23972861
Additional file 3 of Microglial responses to CSF1 overexpression do not promote the expansion of other glial lineages
De, I., Maklakova, V. I., Litscher, S. J., Boyd, M. M., Klemm, L. C., Wang, Z., Kendziorski, C. M., & Collier, L. S. (2021) · Figshare · doi:10.6084/m9.figshare.15020534
Additional file 7 of Microglial responses to CSF1 overexpression do not promote the expansion of other glial lineages
De, I., Maklakova, V. I., Litscher, S. J., Boyd, M. M., Klemm, L. C., Wang, Z., Kendziorski, C. M., & Collier, L. S. (2021) · Figshare · doi:10.6084/m9.figshare.15020546
Additional file 6 of Microglial responses to CSF1 overexpression do not promote the expansion of other glial lineages
De, I., Maklakova, V. I., Litscher, S. J., Boyd, M. M., Klemm, L. C., Wang, Z., Kendziorski, C. M., & Collier, L. S. (2021) · Figshare · doi:10.6084/m9.figshare.15020543
Additional file 2 of Microglial responses to CSF1 overexpression do not promote the expansion of other glial lineages
De, I., Maklakova, V. I., Litscher, S. J., Boyd, M. M., Klemm, L. C., Wang, Z., Kendziorski, C. M., & Collier, L. S. (2021) · Figshare · doi:10.6084/m9.figshare.15020531
Additional file 1 of Microglial responses to CSF1 overexpression do not promote the expansion of other glial lineages
De, I., Maklakova, V. I., Litscher, S. J., Boyd, M. M., Klemm, L. C., Wang, Z., Kendziorski, C. M., & Collier, L. S. (2021) · Figshare · doi:10.6084/m9.figshare.15020528
Additional file 4 of Microglial responses to CSF1 overexpression do not promote the expansion of other glial lineages
De, I., Maklakova, V. I., Litscher, S. J., Boyd, M. M., Klemm, L. C., Wang, Z., Kendziorski, C. M., & Collier, L. S. (2021) · Figshare · doi:10.6084/m9.figshare.15020537
Additional file 2 of Microglial senescence contributes to female-biased neuroinflammation in the aging mouse hippocampus: implications for Alzheimer’s disease
Ocañas, S. R., Pham, K. D., Cox, J. E. J., Keck, A. W., Ko, S., Ampadu, F. A., Porter, H. L., Ansere, V. A., Kulpa, A. M., Kellogg, C. M., et al. (2023) · Figshare · doi:10.6084/m9.figshare.23972855
Additional file 4 of Minocycline protects against microgliopathy in a Csf1r haplo-insufficient mouse model of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP)
Li, X., Hu, B., Xiaoyan, G., Wang, Z., Zhou, Y., Sun, H., Zhang, X., Li, Y., Huang, X., Zhao, Y., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26593169
Additional file 6 of Minocycline protects against microgliopathy in a Csf1r haplo-insufficient mouse model of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP)
Li, X., Hu, B., Xiaoyan, G., Wang, Z., Zhou, Y., Sun, H., Zhang, X., Li, Y., Huang, X., Zhao, Y., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26593175
Additional file 5 of Minocycline protects against microgliopathy in a Csf1r haplo-insufficient mouse model of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP)
Li, X., Hu, B., Xiaoyan, G., Wang, Z., Zhou, Y., Sun, H., Zhang, X., Li, Y., Huang, X., Zhao, Y., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26593172
Additional file 4 of Microglial senescence contributes to female-biased neuroinflammation in the aging mouse hippocampus: implications for Alzheimer’s disease
Ocañas, S. R., Pham, K. D., Cox, J. E. J., Keck, A. W., Ko, S., Ampadu, F. A., Porter, H. L., Ansere, V. A., Kulpa, A. M., Kellogg, C. M., et al. (2023) · Figshare · doi:10.6084/m9.figshare.23972864
Additional file 1 of Microglial senescence contributes to female-biased neuroinflammation in the aging mouse hippocampus: implications for Alzheimer’s disease
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Additional file 2 of Single cell analysis reveals the roles and regulatory mechanisms of type-I interferons in Parkinson’s disease
Quan, P., Li, X., Si, Y., Sun, L., Ding, F. F., Fan, Y., Liu, H., Wei, C., Li, R., Zhao, X., et al. (2024) · Figshare · doi:10.6084/m9.figshare.25530423
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Authors: Goldmann, T., Zeller, N., Raasch, J., Kierdorf, K., Frenzel, K., Ketscher, L., Basters, A., Staszewski, O., Brendecke, S. M., Spiess, A., Tay, T. L., Kreutz, C., Timmer, J., Mancini, G. M., Blank, T., Fritz, G., Biber, K., Lang, R., Malo, D., Merkler, D., Heikenwälder, M., Knobeloch, K., & Prinz, M.
Affiliations: University of Freiburg (DE)
Erasmus MC (NL)
University Medical Center Groningen (NL)
Universitätsklinikum Erlangen (DE)
McGill University (CA)
University of Geneva (CH)
Helmholtz Munich (DE)
Corresponding author: Prinz, Marco
ORCID: Goldmann, Tobias
Kierdorf, Katrin
Ketscher, Lars
Basters, Anja
Staszewski, Ori
Brendecke, Stefanie M
Tay, Tuan Leng
Kreutz, Clemens
Timmer, Jens
Blank, Thomas
Fritz, Günter
Biber, Knut
Lang, Roland
Malo, Danielle
Merkler, Doron
Heikenwälder, Mathias
Knobeloch, Klaus‐Peter
Prinz, Marco
Venue: The EMBO Journal
Publisher: Springer Science and Business Media LLC
Published: 2015-04-20
Volume: 34
Issue: 12
Pages: 1612-1629
ISSN: 0261-4189 (ISSN-L)
1460-2075
DOI: 10.15252/embj.201490791
PMC: PMC4475397
OpenAlex: W2097365950
Cited by: 223
References: 60
Citations by year: 2026: 14 · 2025: 19 · 2024: 15 · 2023: 23 · 2022: 11 · 2021: 35 · 2020: 22 · 2019: 25 · 2018: 15 · 2017: 22 · 2016: 14 · 2015: 7
FWCI: 10.33
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: The EMBO Journal (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
Archive ouverte UNIGE (University of Geneva) (publishedVersion)
EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
FreiDok plus (Universitätsbibliothek Freiburg) (submittedVersion)
mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
Site cant be reached (submittedVersion)
University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
RePub (Erasmus University Rotterdam) (submittedVersion)
Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
Funders: BMBF‐funded competence network of multiple sclerosis
DFG (SFB 992, FOR1336, ZE 894/1‐1, PR 577/8‐1, KN590/3‐2 (SPP1365), KN590/1‐3)
Fritz‐Thyssen Foundation
Sobek Foundation
Gemeinnützige Hertie Foundation
ERA‐Net NEURON initiative “NEURO‐IFN”
Canadian Institutes of Health Research (CTP‐87520)
Swiss National Science Foundation (PP00P3_152928)
Klaus‐Tschira Foundation
Gebert‐Rüf Foundation
Topics: Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
Keywords: USP18, microglia, interferon signaling, STAT1, IFNAR2, IFNAR1, deubiquitination, microglial activation, neuroinflammation, interferonopathies, anti-inflammatory regulation
MeSH terms: Animals, Brain, Cloning, Molecular, Histological Techniques, Interferons, Microscopy, Fluorescence, Models, Neurological, Endopeptidases, Blotting, Western, Signal Transduction, Microglia, DNA Primers, Mice, Knockout, Statistics, Nonparametric, Ubiquitin Thiolesterase, Microarray Analysis, Microscopy, Electron, Transmission, Mice, Real-Time Polymerase Chain Reaction

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USP18 lack in microglia causes destructive interferonopathy of the mouse brain

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