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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2019.02713

Dual deletion of the sirtuins SIRT2 and SIRT3 impacts on metabolism and inflammatory responses of macrophages and protects from endotoxemia

 Tytti Heinonen1,  Eleonora Ciarlo1, Ersilia Rigoni1, Jean Regina1,  Didier LE ROY1 and  Thierry Roger1*
  • 1Lausanne University Hospital (CHUV), Switzerland

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 than that of SIRT2/3+/+ mice. 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 that be considered for drug development. Moreover, inhibitors targeting multiple sirtuins developed for clinical purposes may be useful to treat inflammatory diseases.

Keywords: Sirtuins, SIRT2, sirt3, innate immunity, macrophage, Phagocytosis, Sepsis, cytokine, Inflammation, Metabolism, Endotoxemia

Received: 30 Jul 2019; Accepted: 05 Nov 2019.

Copyright: © 2019 Heinonen, Ciarlo, Rigoni, Regina, LE ROY and Roger. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Thierry Roger, Lausanne University Hospital (CHUV), Lausanne, 1011, Vaud, Switzerland, Thierry.Roger@chuv.ch