Sirtuin 3 deficiency does not alter host defenses against bacterial and fungal infections

Eleonora Ciarlo,Johan Auwerx,Didier Le Roy,Jérôme Lugrin,Tytti Heinonen,Hans Acha-Orbea,Thierry Roger

doi:10.1038/s41598-017-04263-x

Eleonora Ciarlo, Johan Auwerx + Show 5 more

Open Access

https://doi.org/10.1038/s41598-017-04263-x

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Abstract

Sirtuin 3 (SIRT3) is the main mitochondrial deacetylase. SIRT3 regulates cell metabolism and redox homeostasis, and protects from aging and age-associated pathologies. SIRT3 may drive both oncogenic and tumor-suppressive effects. SIRT3 deficiency has been reported to promote chronic inflammation-related disorders, but whether SIRT3 impacts on innate immune responses and host defenses against infections remains essentially unknown. This aspect is of primary importance considering the great interest in developing SIRT3-targeted therapies. Using SIRT3 knockout mice, we show that SIRT3 deficiency does not affect immune cell development and microbial ligand-induced proliferation and cytokine production by splenocytes, macrophages and dendritic cells. Going well along with these observations, SIRT3 deficiency has no major impact on cytokine production, bacterial burden and survival of mice subjected to endotoxemia, Escherichia coli peritonitis, Klebsiella pneumoniae pneumonia, listeriosis and candidiasis of diverse severity. These data suggest that SIRT3 is not critical to fight infections and support the safety of SIRT3-directed therapies based on SIRT3 activators or inhibitors for treating metabolic, oncologic and neurodegenerative diseases without putting patients at risk of infection.

Highlights

The innate immune system provides the first line of defense against microbial infections
We report that Sirtuin 3 (SIRT3) deficiency has no major impact on immune cell development and host defenses against bacterial and fungal infections
SIRT3 deficiency did not alter the composition of the main lymphoid and dendritic cells (DCs) subsets in thymus and spleen, in line with a previous study showing normal thymic, splenic and lymph node CD4+ and CD8+ T-cell subpopulations in SIRT3−/− mice, including CD4+ Foxp3+ T regulatory cells (Tregs)[29]

Summary

Introduction

The innate immune system provides the first line of defense against microbial infections. As a regulator of metabolism and oxidative stress homeostasis, SIRT3 protects from aging and age-associated dysfunctions, and genetic studies identified SIRT3 polymorphisms associated with increased longevity[17,18,19,20]. All these observations stimulated the development of both activators and inhibitors of SIRT3 for clinical purposes[40]. Within this context, it is important to ascertain that SIRT3 targeting would not negatively impact on host resistance to infection, an aspect of SIRT3 biology that is so far poorly characterized[41, 42]

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