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Nat Commun. 2018 May 23;9(1):2036. doi: 10.1038/s41467-018-04376-5.

A20 critically controls microglia activation and inhibits inflammasome-dependent neuroinflammation.

Author information

1
VIB Center for Inflammation Research, B-9052, Ghent, Belgium.
2
Department of Biomedical Molecular Biology, Ghent University, B-9052, Ghent, Belgium.
3
VIB Center for Medical Biotechnology, B-9052, Ghent, Belgium.
4
Department of Biochemistry and Microbiology, Ghent University, B-9052, Ghent, Belgium.
5
Institute of Neuropathology, Faculty of Medicine, University of Freiburg, D-79106, Freiburg, Germany.
6
VIB Center for Brain & Disease Research, B-3000, Leuven, Belgium.
7
Department of Neurosciences, KU Leuven, B-3000, Leuven, Belgium.
8
Institute of Anatomy, University of Leipzig, Leipzig, D-04103, Germany.
9
Department of Human Genetics, KU Leuven, B-3000, Leuven, Belgium.
10
Department of Internal Medicine, Ghent University, B-9052, Ghent, Belgium.
11
VIB Bio-Imaging Core, B-9052, Ghent, Belgium.
12
Department of Immunology, Weizmann Institute of Science, I-76100, Rehovot, Israel.
13
Department of Pathology and Immunology, Washington University of Medicine, St. Louis, MO, 63110, USA.
14
Laboratory of Biological Psychology, KU Leuven, B-3000, Leuven, Belgium.
15
BIOSS Centre for Biological Signalling Studies, University of Freiburg, D79106, Freiburg, Germany.
16
VIB Center for Inflammation Research, B-9052, Ghent, Belgium. geert.vanloo@irc.vib-ugent.be.
17
Department of Biomedical Molecular Biology, Ghent University, B-9052, Ghent, Belgium. geert.vanloo@irc.vib-ugent.be.

Abstract

Microglia, the mononuclear phagocytes of the central nervous system (CNS), are important for the maintenance of CNS homeostasis, but also critically contribute to CNS pathology. Here we demonstrate that the nuclear factor kappa B (NF-κB) regulatory protein A20 is crucial in regulating microglia activation during CNS homeostasis and pathology. In mice, deletion of A20 in microglia increases microglial cell number and affects microglial regulation of neuronal synaptic function. Administration of a sublethal dose of lipopolysaccharide induces massive microglia activation, neuroinflammation, and lethality in mice with microglia-confined A20 deficiency. Microglia A20 deficiency also exacerbates multiple sclerosis (MS)-like disease, due to hyperactivation of the Nlrp3 inflammasome leading to enhanced interleukin-1β secretion and CNS inflammation. Finally, we confirm a Nlrp3 inflammasome signature and IL-1β expression in brain and cerebrospinal fluid from MS patients. Collectively, these data reveal a critical role for A20 in the control of microglia activation and neuroinflammation.

PMID:
29789522
PMCID:
PMC5964249
DOI:
10.1038/s41467-018-04376-5
[Indexed for MEDLINE]
Free PMC Article

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