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Frontiers in immunology · Jan 2019
Dual Deletion of the Sirtuins SIRT2 and SIRT3 Impacts on Metabolism and Inflammatory Responses of Macrophages and Protects From Endotoxemia.
- Tytti Heinonen, Eleonora Ciarlo, Ersilia Rigoni, Jean Regina, Didier Le Roy, and Thierry Roger.
- Infectious Diseases Service, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
- Front Immunol. 2019 Jan 1; 10: 2713.
AbstractSirtuin 2 (SIRT2) and SIRT3 are cytoplasmic and mitochondrial NAD-dependent deacetylases. SIRT2 and SIRT3 target proteins involved in metabolic, proliferation and inflammation pathways and have been implicated in the pathogenesis of neurodegenerative, metabolic and oncologic disorders. Both pro- and anti-inflammatory effects have been attributed to SIRT2 and SIRT3, and single deficiency in SIRT2 or SIRT3 had minor or no impact on antimicrobial innate immune responses. Here, we generated a SIRT2/3 double deficient mouse line to study the interactions between SIRT2 and SIRT3. SIRT2/3-/- mice developed normally and showed subtle alterations of immune cell populations in the bone marrow, thymus, spleen, blood and peritoneal cavity that contained notably more anti-inflammatory B-1a cells and less NK cells. In vitro, SIRT2/3-/- macrophages favored fatty acid oxidation (FAO) over glycolysis and produced increased levels of both proinflammatory and anti-inflammatory cytokines. In line with metabolic adaptation and increased numbers of peritoneal B-1a cells, SIRT2/3-/- mice were robustly protected from endotoxemia. Yet, SIRT2/3 double deficiency did not modify endotoxin tolerance. Overall, these data suggest that sirtuins can act in concert or compensate each other for certain immune functions, a parameter to be considered for drug development. Moreover, inhibitors targeting multiple sirtuins developed for clinical purposes may be useful to treat inflammatory diseases.Copyright © 2019 Heinonen, Ciarlo, Rigoni, Regina, Le Roy and Roger.
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