Abstract
The sirtuins SIRT3 and SIRT5 are the main mitochondrial lysine deacetylase and desuccinylase, respectively. SIRT3 and SIRT5 regulate metabolism and redox homeostasis and have been involved in age-associated metabolic, neurologic and oncologic diseases. We have previously shown that single deficiency in either SIRT3 or SIRT5 had no impact on host defenses in a large panel of preclinical models of sepsis. However, SIRT3 and SIRT5 may compensate each other considering that they share subcellular location and targets. Here, we generated a SIRT3/5 double knockout mouse line. SIRT3/5 deficient mice multiplied and developed without abnormalities. Hematopoiesis and immune cell development were largely unaffected in SIRT3/5 deficient mice. Whole blood, macrophages and neutrophils from SIRT3/5 deficient mice displayed enhanced inflammatory and bactericidal responses. In agreement, SIRT3/5 deficient mice showed somewhat improved resistance to Listeria monocytogenes infection. Overall, the double deficiency in SIRT3 and SIRT5 has rather subtle impacts on immune cell development and anti-microbial host defenses unseen in single deficient mice, indicating a certain degree of overlap between SIRT3 and SIRT5. These data support the assumption that therapies directed against mitochondrial sirtuins, at least SIRT3 and SIRT5, should not impair antibacterial host defenses.
Highlights
The innate immune system plays a central role in host defenses
The dual deletion of SIRT3 and SIRT5 was not compensated by an increased expression of mRNA encoding for SIRT1, SIRT2, SIRT4, SIRT6, and SIRT7 in bone marrow derived macrophages (BMDMs) (Figure 1F)
There was no statistically significant difference between the SIRT3/5+/+ and SIRT3/5−/− groups (n = 21–22 mice per group; P = 0.1). This is the first report about the impact of the dual deficiency of SIRT3 and SIRT5 on immune cell development and antimicrobial host defenses
Summary
The innate immune system plays a central role in host defenses. Innate immune cells among which monocytes/macrophages, granulocytes and dendritic cells (DCs) sense microbial and danger associated molecular patterns (MAMPs/DAMPs) through pattern recognition receptors (PRRs) expressed at the cell surface, in the cytoplasm and in endosomes. Similar to SIRT3, SIRT5 activates enzymes involved in ROS detoxification (i.e., SOD1, IDH1, and IDH2), promotes mitochondrial functions and integrity and regulates the urea cycle and other metabolic pathways [14, 19,20,21,22,23,24,25]. Considering that inflammation is an essential component of innate immune defenses, we analyzed the impact of SIRT3 and SIRT5 deficiencies on the response of mice subjected to a broad panel of preclinical models of bacterial and fungal sepsis [37, 38]. SIRT3 and SIRT5 share subcellular location and targets, so they might compensate each other in single knockout mice. Therapies directed against mitochondrial sirtuins should not dramatically impact on antimicrobial host defenses
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