title: The NAD-dependent deacetylase sirtuin 2 is a suppressor of microglial activation and brain inflammation.
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.
authors.affiliation: Cell and Molecular Neuroscience Unit, Instituto de Medicina Molecular, Lisboa, Portugal.
authors.forename: Teresa Faria
authors.initials: TF
authors.lastname: Pais
authors.forename: Éva M
authors.initials: ÉM
authors.lastname: Szegő
authors.forename: Oldriska
authors.initials: O
authors.lastname: Marques
authors.forename: Leonor
authors.initials: L
authors.lastname: Miller-Fleming
authors.forename: Pedro
authors.initials: P
authors.lastname: Antas
authors.forename: Patrícia
authors.initials: P
authors.lastname: Guerreiro
authors.forename: Rita Machado
authors.initials: RM
authors.lastname: de Oliveira
authors.forename: Burcu
authors.initials: B
authors.lastname: Kasapoglu
authors.forename: Tiago Fleming
authors.initials: TF
authors.lastname: Outeiro
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002460:Cell Line; D002478:Cells, Cultured; D004660:Encephalitis / Q000276:immunology*; D015850:Interleukin-6 / Q000276:immunology; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000276:immunology*; D016328:NF-kappa B / Q000276:immunology; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D056565:Sirtuin 2 / Q000276:immunology*; D051193:Toll-Like Receptors / Q000276:immunology
chemical_list: D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D051193:Toll-Like Receptors; C418743:Sirt2 protein, mouse; D056565:Sirtuin 2