Journal
FRONTIERS IN IMMUNOLOGY
Volume 10, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2019.02713
Keywords
sirtuins; innate immunity; macrophage; sepsis; cytokine; inflammation; metabolism; endotoxemia
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Funding
- Swiss National Science Foundation (SNSF) [145014, 149511, 173123]
- Faculty of Biology and Medicine of the University of Lausanne (Switzerland)
- Societe Academique Vaudoise (Lausanne, Switzerland)
- Swiss-European Mobility Programme (SEMP)
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Sirtuin 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.
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