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.

SIRT2 Regulates LPS-Induced Renal Tubular CXCL2 and CCL2 Expression

“…8,10 In this study, we demonstrated that deficiency of SIRT2 is crucially associated with LPS-induced renal inflammation. In particular, SIRT2 regulated inflammatory signaling through the MKP-1 and MAPK axis.…”

“…9 Recently, investigators reported that SIRT2 helps regulate the inflammatory process in brain microglial cells. 10 Those authors have demonstrated that a decrease of SIRT2 potentiates the LPS and TNF-a-induced expression of proinflammatory cytokines, such as IL-6, macrophage activating 2 like, and IFN-g-induced protein 10, in brain microglial cells.…”

Molecular Regulation of Cell Fate in Cerebral Ischemia: Role of the Inflammasome and Connected Pathways

“…119 Sirt2 has been demonstrated to be a repressor of microglial activation and brain inflammation. 125 Aberrant mitochondrial homeostasis diminishes the coenzyme NAD + levels, leads to reduced Sirt2 activity, increases the level of acetylation of microtubules, and thereby causes NLRP3-inflammasome activation by a dyneinmediated transport of ASC on mitochondria to NLRP3 on the endoplasmic reticulum. 19 Dietary fatty acids have been demonstrated to mediate systemic inflammation and insulin resistance via innate immune receptors, and palmitic acid, the major saturated fatty acid, was shown to induce NLRP3 expression via TLR2-activation and induces inflammasome-mediated IL-1β production in human monocytes.…”

Changes in sirtuin 2 and sirtuin 3 mRNA expressions in rheumatoid arthritis

“…SIRT1, SIRT2, and SIRT6 have been reported to suppress NF-κB activation by deacetylating p65 (11,12,25,26). Therefore, they have anti-inflammatory roles.…”

“…Pais et al (25) documented that lipopolysaccharide-induced inflammation decreases SIRT2 mRNA expressions in the brain. Caton et al (31) also reported that the incubation of pancreatic islet cells with pro-inflammatory cytokines, including IL-1β and TNFα, decreases SIRT3 mRNA expression.…”