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The NAD-dependent deacetylase sirtuin 2 is a suppressor of microglial activation and brain inflammation

Lookup NU author(s): Professor Tiago OuteiroORCiD

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Abstract

Deleterious sustained inflammation mediated by activated microglia is common to most of neurologic disorders. Here, we identified sirtuin 2 (SIRT2), an abundant deacetylase in the brain, as a major inhibitor of microglia-mediated inflammation and neurotoxicity. SIRT2-deficient mice (SIRT2-/-) showed morphological changes in microglia and an increase in pro-inflammatory cytokines upon intracortical injection of lipopolysaccharide (LPS). This response was associated with increased nitrotyrosination and neuronal cell death. Interestingly, manipulation of SIRT2 levels in microglia determined the response to Toll-like receptor (TLR) activation. SIRT2 overexpression inhibited microglia activation in a process dependent on serine 331 (S331) phosphorylation. Conversely, reduction of SIRT2 in microglia dramatically increased the expression of inflammatory markers, the production of free radicals, and neurotoxicity. Consistent with increased NF-κB-dependent transcription of inflammatory genes, NF-κB was found hyperacetylated in the absence of SIRT2, and became hypoacetylated in the presence of S331A mutant SIRT2. This finding indicates that SIRT2 functions as a 'gatekeeper', preventing excessive microglial activation through NF-κB deacetylation. Our data uncover a novel role for SIRT2 opening new perspectives for therapeutic intervention in neuroinflammatory disorders. © 2013 European Molecular Biology Organization.

Publication metadata

Author(s): Pais TF, Szego EM, Marques O, Miller-Fleming L, Antas P, Guerreiro P, De Oliveira RM, Kasapoglu B, Outeiro TF

Publication type: Article

Publication status: Published

Journal: EMBO Journal

Year: 2013

Volume: 32

Issue: 19

Pages: 2603-2616

Online publication date: 06/09/2013

ISSN (print): 0261-4189

ISSN (electronic): 1460-2075

Publisher: Wiley-Blackwell Publishing Ltd.

URL: https://doi.org/10.1038/emboj.2013.200

DOI: 10.1038/emboj.2013.200

PubMed id: 24013120

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