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Sirtuin 2 Deficiency Increases Bacterial Phagocytosis by Macrophages and Protects from Chronic Staphylococcal Infection
Sirtuin 2 (SIRT2) is one of the seven members of the family of NAD(+)-dependent histone deacetylases. Sirtuins target histones and non-histone proteins according to their subcellular localization, influencing various biological processes. SIRT2 resides mainly in the cytoplasm and regulates cytoskele...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5581327/ https://www.ncbi.nlm.nih.gov/pubmed/28894448 http://dx.doi.org/10.3389/fimmu.2017.01037 |
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author | Ciarlo, Eleonora Heinonen, Tytti Théroude, Charlotte Herderschee, Jacobus Mombelli, Matteo Lugrin, Jérôme Pfefferlé, Marc Tyrrell, Beatrice Lensch, Sarah Acha-Orbea, Hans Le Roy, Didier Auwerx, Johan Roger, Thierry |
author_facet | Ciarlo, Eleonora Heinonen, Tytti Théroude, Charlotte Herderschee, Jacobus Mombelli, Matteo Lugrin, Jérôme Pfefferlé, Marc Tyrrell, Beatrice Lensch, Sarah Acha-Orbea, Hans Le Roy, Didier Auwerx, Johan Roger, Thierry |
author_sort | Ciarlo, Eleonora |
collection | PubMed |
description | Sirtuin 2 (SIRT2) is one of the seven members of the family of NAD(+)-dependent histone deacetylases. Sirtuins target histones and non-histone proteins according to their subcellular localization, influencing various biological processes. SIRT2 resides mainly in the cytoplasm and regulates cytoskeleton dynamics, cell cycle, and metabolic pathways. As such, SIRT2 has been implicated in the pathogenesis of neurodegenerative, metabolic, oncologic, and chronic inflammatory disorders. This motivated the development of SIRT2-directed therapies for clinical purposes. However, the impact of SIRT2 on antimicrobial host defense is largely unknown. Here, we address this question using SIRT2 knockout mice. We show that SIRT2 is the most highly expressed sirtuin in myeloid cells, especially macrophages. SIRT2 deficiency does not affect immune cell development and marginally impacts on intracellular signaling and cytokine production by splenocytes and macrophages. However, SIRT2 deficiency enhances bacterial phagocytosis by macrophages. In line with these observations, in preclinical models, SIRT2 deficiency increases survival of mice with chronic staphylococcal infection, while having no effect on the course of toxic shock syndrome toxin-1, LPS or TNF-induced shock, fulminant Escherichia coli peritonitis, sub-lethal Klebsiella pneumoniae pneumonia, and chronic candidiasis. Altogether, these data support the safety profile of SIRT2 inhibitors under clinical development in terms of susceptibility to infections. |
format | Online Article Text |
id | pubmed-5581327 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-55813272017-09-11 Sirtuin 2 Deficiency Increases Bacterial Phagocytosis by Macrophages and Protects from Chronic Staphylococcal Infection Ciarlo, Eleonora Heinonen, Tytti Théroude, Charlotte Herderschee, Jacobus Mombelli, Matteo Lugrin, Jérôme Pfefferlé, Marc Tyrrell, Beatrice Lensch, Sarah Acha-Orbea, Hans Le Roy, Didier Auwerx, Johan Roger, Thierry Front Immunol Immunology Sirtuin 2 (SIRT2) is one of the seven members of the family of NAD(+)-dependent histone deacetylases. Sirtuins target histones and non-histone proteins according to their subcellular localization, influencing various biological processes. SIRT2 resides mainly in the cytoplasm and regulates cytoskeleton dynamics, cell cycle, and metabolic pathways. As such, SIRT2 has been implicated in the pathogenesis of neurodegenerative, metabolic, oncologic, and chronic inflammatory disorders. This motivated the development of SIRT2-directed therapies for clinical purposes. However, the impact of SIRT2 on antimicrobial host defense is largely unknown. Here, we address this question using SIRT2 knockout mice. We show that SIRT2 is the most highly expressed sirtuin in myeloid cells, especially macrophages. SIRT2 deficiency does not affect immune cell development and marginally impacts on intracellular signaling and cytokine production by splenocytes and macrophages. However, SIRT2 deficiency enhances bacterial phagocytosis by macrophages. In line with these observations, in preclinical models, SIRT2 deficiency increases survival of mice with chronic staphylococcal infection, while having no effect on the course of toxic shock syndrome toxin-1, LPS or TNF-induced shock, fulminant Escherichia coli peritonitis, sub-lethal Klebsiella pneumoniae pneumonia, and chronic candidiasis. Altogether, these data support the safety profile of SIRT2 inhibitors under clinical development in terms of susceptibility to infections. Frontiers Media S.A. 2017-08-28 /pmc/articles/PMC5581327/ /pubmed/28894448 http://dx.doi.org/10.3389/fimmu.2017.01037 Text en Copyright © 2017 Ciarlo, Heinonen, Théroude, Herderschee, Mombelli, Lugrin, Pfefferlé, Tyrrell, Lensch, Acha-Orbea, Le Roy, Auwerx and Roger. http://creativecommons.org/licenses/by/4.0/ 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) or licensor 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. |
spellingShingle | Immunology Ciarlo, Eleonora Heinonen, Tytti Théroude, Charlotte Herderschee, Jacobus Mombelli, Matteo Lugrin, Jérôme Pfefferlé, Marc Tyrrell, Beatrice Lensch, Sarah Acha-Orbea, Hans Le Roy, Didier Auwerx, Johan Roger, Thierry Sirtuin 2 Deficiency Increases Bacterial Phagocytosis by Macrophages and Protects from Chronic Staphylococcal Infection |
title | Sirtuin 2 Deficiency Increases Bacterial Phagocytosis by Macrophages and Protects from Chronic Staphylococcal Infection |
title_full | Sirtuin 2 Deficiency Increases Bacterial Phagocytosis by Macrophages and Protects from Chronic Staphylococcal Infection |
title_fullStr | Sirtuin 2 Deficiency Increases Bacterial Phagocytosis by Macrophages and Protects from Chronic Staphylococcal Infection |
title_full_unstemmed | Sirtuin 2 Deficiency Increases Bacterial Phagocytosis by Macrophages and Protects from Chronic Staphylococcal Infection |
title_short | Sirtuin 2 Deficiency Increases Bacterial Phagocytosis by Macrophages and Protects from Chronic Staphylococcal Infection |
title_sort | sirtuin 2 deficiency increases bacterial phagocytosis by macrophages and protects from chronic staphylococcal infection |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5581327/ https://www.ncbi.nlm.nih.gov/pubmed/28894448 http://dx.doi.org/10.3389/fimmu.2017.01037 |
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