Dataset Information

Sirtuin 5 Deficiency Does Not Compromise Innate Immune Responses to Bacterial Infections.

ABSTRACT: Sirtuin 5 (SIRT5) is a member of the family of NAD+-dependent lysine/histone deacetylases. SIRT5 resides mainly in the mitochondria where it catalyzes deacetylation, demalonylation, desuccinylation, and deglutarylation of lysine to regulate metabolic and oxidative stress response pathways. Pharmacologic inhibitors of SIRT5 are under development for oncologic conditions, but nothing is known about the impact of SIRT5 on antimicrobial innate immune defenses. Using SIRT5 knockout mice, we show that SIRT5 deficiency does not affect immune cell development, cytokine production and proliferation by macrophages and splenocytes exposed to microbial and immunological stimuli. Moreover, preclinical models suggest that SIRT5 deficiency does not worsen endotoxemia, Klebsiella pneumoniae and Streptococcus pneumoniae pneumonia, Escherichia coli peritonitis, listeriosis, and staphylococcal infection. Altogether, these data support the safety profile in terms of susceptibility to infections of SIRT5 inhibitors under development.

SUBMITTER: Heinonen T

PROVIDER: S-EPMC6255879 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Sirtuin 5 Deficiency Does Not Compromise Innate Immune Responses to Bacterial Infections.

Heinonen Tytti T Ciarlo Eleonora E Théroude Charlotte C Pelekanou Aimilia A Herderschee Jacobus J Le Roy Didier D Roger Thierry T

Frontiers in immunology 20181120

Sirtuin 5 (SIRT5) is a member of the family of NAD<sup>+</sup>-dependent lysine/histone deacetylases. SIRT5 resides mainly in the mitochondria where it catalyzes deacetylation, demalonylation, desuccinylation, and deglutarylation of lysine to regulate metabolic and oxidative stress response pathways. Pharmacologic inhibitors of SIRT5 are under development for oncologic conditions, but nothing is known about the impact of SIRT5 on antimicrobial innate immune defenses. Using SIRT5 knockout mice, w ...[more]

PMID: 30515162

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Project description:Deficiency in the protein-tyrosine phosphatase SHP1/PTPN6 is linked with hematological malignancies and chronic inflammatory diseases. Here we exploited the embryonic and larval stages of zebrafish as an animal model to study ptpn6 function in the sole context of innate immunity. We show that ptpn6 knockdown induces a spontaneous inflammation-associated phenotype at the late larval stage, which was microbe-independent and enhanced instead of suppressed by glucocorticoids. When challenged with Salmonella typhimurium or Mycobacterium marinum at earlier stages of development, the innate immune system was hyperactivated to a contra-productive level that impaired the control of these pathogenic bacteria. These results demonstrate the crucial regulatory function of ptpn6 in preventing host-detrimental effects of inflammation by imposing a tight control over the level of innate immune response activation. This microarray study was designed to determine the effect of morpholino knockdown of the ptpn6 gene on the innate immune response of zebrafish embryos during infection with Salmonella typhimurium. Three independent infection experiments were performed using mixed egg clutches of wild type zebrafish, which were a cross of the AB and TL strains. Each experiment consisted of the following four treatment groups: (1) uninfected control embryos, (2) S. typhimurium-infected control embryos, (3) uninfected ptpn6 knockdown embryos, and (4) S. typhimurium-infected ptpn6 knockdown embryos. Knockdown of ptpn6 was performed by micro-injecting embryos at the 1-2 cell stage with the ptpn6 morpholino, and control embryos were mock-injected with buffer. Embryos were grown at 28.5M-bM-^@M-^S30M-BM-0C in egg water and manually dechorionated at 24 hours post fertilization (hpf). Subsequently, embryos were infected at 28 hpf by micro-injecting 200-250 colony forming units (CFU) of S. typhimurium SL1027 bacteria into the caudal vein, or were mock-injected with buffer as a control. After injections embryos were transferred into fresh egg water and incubated for 8 h at 28M-BM-0C. After the incubation period, pools of 15-20 embryos per treatment group were snap-frozen in liquid nitrogen and RNA was isolated for microarray analysis. All treatment groups were analyzed using a common reference approach.

Dataset Information

Sirtuin 5 Deficiency Does Not Compromise Innate Immune Responses to Bacterial Infections.

Publications

Sirtuin 5 Deficiency Does Not Compromise Innate Immune Responses to Bacterial Infections.

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