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The NAD-dependent deacetylase sirtuin

2 is a suppressor of microglial activation and brain in?ammation Teresa Faria Pais1, *, E ?va M Szeg+ o2 , Oldriska Marques1 , Leonor Miller-Fleming1 , Pedro Antas1 , Patr??cia Guerreiro1 , Rita Machado de Oliveira1 , Burcu Kasapoglu3 and Tiago Fleming Outeiro1,2,4, *

1 Cell and Molecular Neuroscience Unit, Instituto de Medicina Molecular, Lisboa, Portugal,

2 Department of Neurodegeneration and Restorative Research, University Medical Center Go ¨ttingen, Go ¨ttingen, Germany,

3 Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Go ¨ttingen, Germany and

4 Instituto de Fisiologia, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal Deleterious sustained in?ammation mediated by activated microglia is common to most of neurologic disorders.

Here, we identi?ed sirtuin

2 (SIRT2), an abundant deacetylase in the brain, as a major inhibitor of microglia-mediated in?ammation and neurotoxicity. SIRT2-de?cient mice (SIRT2? / ? ) showed morphological changes in microglia and an increase in pro-in?ammatory 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 in?ammatory markers, the production of free radicals, and neurotoxicity. Consistent with increased NF-jB- dependent transcription of in?ammatory genes, NF-jB was found hyperacetylated in the absence of SIRT2, and became hypoacetylated in the presence of S331A mutant SIRT2. This ?nding indicates that SIRT2 functions as a '

gatekeeper'

, preventing excessive microglial activation through NF-jB deacetylation. Our data uncover a novel role for SIRT2 opening new perspectives for therapeutic intervention in neuroin?ammatory disorders. The EMBO Journal (2013) 32, 2603C2616. doi:10.1038/ emboj.2013.200;

Published online

6 September

2013 Subject Categories: neuroscience;

immunology Keywords: brain;

in?ammation;

microglia Introduction Microglia, the innate immune cells in the CNS, are adapted to sense and immediately react to pathogens, misfolded proteins, or molecules released by damaged cells. It is now known that microglia may adopt different activated pheno- types in response to external stimuli. Whether activated microglia is bene?cial or noxious to the CNS is determined by several variables, including the balance between cytotoxic and neurotrophic molecules generated by activated microglia, and the intensity and timing of microglial activation (reviewed in Lucin and Wyss-Coray, 2009;

Perry et al, 2010;

and Saijo and Glass, 2011). A deleterious sustained in?ammatory response mediated by microglia has been associated to several neurologic conditions, including CNS infections (Garden, 2002;

Dellacasa-Lindberg et al, 2011), ischemic stroke (Yrjanheikki et al, 1998), and neurodegenerative diseases, such as Alzheimer'

s, Parkinson'

s, and Huntington'

s disease (McGeer et al, 1988;

Sulzer, 2007;

Tai et al, 2007). In these diseases, secretion of in?ammatory mediators by microglia, such as pro-in?ammatory cytokines (i.e., tumour necrosis factor (TNF), IL-6, and IL-1b), metalloproteases, reactive oxygen species (ROS), nitric oxide (NO), and glutamate, are thought to contribute to neuronal cell death (Block et al, 2007). Therefore, dissecting the mechanisms that selectively shut off deleterious activation pathways might play an important role in controlling neurologic diseases. In fact, deregulation of microglial receptors CD200R and TREM2 signalling-mediated pathways, which were shown to prevent toxicity of microglia, is associated to increased in?ammation and neurodegeneration in humans (Piccio et al, 2008;