A20 critically controls microglia activation and inhibits inflammasome-dependent neuroinflammation

Sofie Voet, Conor Guire, Nora Hagemeyer, Arne Martens, Anna Schroeder, Peter Wieghofer, Carmen Daems, Ori Staszewski, Lieselotte Vande Walle, Marta Joana Costa Jordao, Mozes Sze, Hanna-Kaisa Vikkula, Delphine Demeestere, Griet Imschoot, Charlotte L. Scott, Esther Hoste, Amanda Gonçalves, Martin Guilliams, Saskia Lippens, Claude Libert, Roos E. Vandenbroucke, Ki-Wook Kim, Steffen Jung, Zsuzsanna Callaerts-Vegh, Patrick Callaerts, Joris Wit, Mohamed Lamkanfi, Marco Prinz and Geert Loo ()
Additional contact information
Sofie Voet: VIB Center for Inflammation Research
Conor Guire: VIB Center for Inflammation Research
Nora Hagemeyer: University of Freiburg
Arne Martens: VIB Center for Inflammation Research
Anna Schroeder: VIB Center for Brain & Disease Research
Peter Wieghofer: University of Freiburg
Carmen Daems: KU Leuven
Ori Staszewski: University of Freiburg
Lieselotte Vande Walle: VIB Center for Inflammation Research
Marta Joana Costa Jordao: University of Freiburg
Mozes Sze: VIB Center for Inflammation Research
Hanna-Kaisa Vikkula: VIB Center for Inflammation Research
Delphine Demeestere: VIB Center for Inflammation Research
Griet Imschoot: VIB Center for Inflammation Research
Charlotte L. Scott: VIB Center for Inflammation Research
Esther Hoste: VIB Center for Inflammation Research
Amanda Gonçalves: VIB Center for Inflammation Research
Martin Guilliams: VIB Center for Inflammation Research
Saskia Lippens: VIB Center for Inflammation Research
Claude Libert: VIB Center for Inflammation Research
Roos E. Vandenbroucke: VIB Center for Inflammation Research
Ki-Wook Kim: Weizmann Institute of Science
Steffen Jung: Weizmann Institute of Science
Zsuzsanna Callaerts-Vegh: KU Leuven
Patrick Callaerts: KU Leuven
Joris Wit: VIB Center for Brain & Disease Research
Mohamed Lamkanfi: VIB Center for Inflammation Research
Marco Prinz: University of Freiburg
Geert Loo: VIB Center for Inflammation Research

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-04376-5

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