Besides histones, sirtuins target thousands of non-histone proteins, among which chromatin modifiers, transcription regulators, signal transduction molecules, metabolic enzymes and structural cell components 3.
Sirtuins (SIRT1–7) belong to the NAD +-dependent class III subfamily of histone deacetylases (HDACs) 2. The interaction between PRRs and microbial ligands activates intracellular signaling pathways that coordinate the expression of immune-regulatory genes among which cytokines/chemokines, and the development of humoral and cellular responses required to neutralize or eliminate pathogens and restore homeostasis. The best-characterized family of PRRs is constituted by Toll-like receptors (TLRs), which mediate the sensing of a broad range of microbial structures 1. Innate immune cells such as macrophages and dendritic cells (DCs) detect invading microorganisms through pattern recognition receptors (PRRs). The innate immune system provides the first line of defense against microbial infections. 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. 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. 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. This aspect is of primary importance considering the great interest in developing SIRT3-targeted therapies. 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. SIRT3 may drive both oncogenic and tumor-suppressive effects. SIRT3 regulates cell metabolism and redox homeostasis, and protects from aging and age-associated pathologies. Sirtuin 3 (SIRT3) is the main mitochondrial deacetylase.
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