Sirtuin 2 Deficiency Increases Bacterial Phagocytosis by Macrophages and Protects from Chronic Staphylococcal Infection

Abstract

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.

Efferocytosis Fuels Requirements of Fatty Acid Oxidation and the Electron Transport Chain to Polarize Macrophages for Tissue Repair

“…given previous links to macrophage polarization and bacterial phagocytosis (Ciarlo et al, 2017); however, Sirt2-deficient phagocytes remained relatively competent at generating IL-10 after efferocytosis ( Figure 6A). This was in contrast to Sirt1, which displayed elevated protein levels after efferocytosis (Figure 6B) and was also required relatively more than Sirt2 for IL-10 generation ( Figure 6C).…”

SIRT3 diminishes inflammation and mitigates endotoxin-induced acute lung injury

“…Sirtuins are histone deacetylases involved in regulating metabolic homeostasis in many cell populations including immune cells (17)(18)(19). In mammals, seven known sirtuins (SIRT1-7) are characterized by distinct subcellular localization and substrate specificity (20).…”

Sirtuin-1 in immunotherapy: A Janus-headed target

“…Sirt2 did not have any notable effect on T‐effector or Treg cell functions in vitro, perhaps because of its cytosolic localization. In myeloid cells, Sirt2 deletion improved bacterial phagocytosis and augmented host responses against staphylococcal infections . On the flip side, Sirt2 –/– mice had increased susceptibility to dextran sodium sulfate induced colitis .…”

“…In myeloid cells, Sirt2 deletion improved bacterial phagocytosis and augmented host responses against staphylococcal infections. 75 On the flip side, Sirt2 -/mice had increased susceptibility to dextran sodium sulfate induced colitis. 76 Sirt3 deletion did not have any overt effect on myeloid and lymphocyte development 20,77 ; however, Sirt3 -/-Treg function was noted to be impaired.…”