SIRT3 promotes antimycobacterial defenses by coordinating mitochondrial and autophagic functions

Abstract

SIRT3 (sirtuin 3), a mitochondrial protein deacetylase, maintains respiratory function, but its role in the regulation of innate immune defense is largely unknown. Herein, we show that SIRT3 coordinates mitochondrial function and macroautophagy/autophagy activation to promote anti-mycobacterial responses through PPARA (peroxisome proliferator activated receptor alpha). SIRT3 deficiency enhanced inflammatory responses and mitochondrial dysfunction, leading to defective host defense and pathological inflammation during mycobacterial infection. Antibody-mediated depletion of polymorphonuclear neutrophils significantly increased protection against mycobacterial infection in sirt3 −/mice. In addition, mitochondrial oxidative stress promoted excessive inflammation induced by Mycobacterium tuberculosis infection in sirt3 −/macrophages. Notably, SIRT3 was essential for the enhancement of PPARA, a key regulator of mitochondrial homeostasis and autophagy activation in the context of infection. Importantly, overexpression of either PPARA or TFEB (transcription factor EB) in sirt3 −/macrophages recovered antimicrobial activity through autophagy activation. Furthermore, pharmacological activation of SIRT3 enhanced antibacterial autophagy and functional mitochondrial pools during mycobacterial infection. Finally, the levels of SIRT3 and PPARA were downregulated and inversely correlated with TNF (tumor necrosis factor) levels in peripheral blood mononuclear cells from tuberculosis patients. Collectively, these data demonstrate a previously unappreciated function of SIRT3 in orchestrating mitochondrial and autophagic functions to promote antimycobacterial responses.

Ninjurin1 deficiency aggravates colitis development by promoting M1 macrophage polarization and inducing microbial imbalance

“…Several colitogenic bacteria promote inflammatory conditions that favor their own growth. Hence, inefficient clearance of bacteria results in non‐resolving inflammation, followed by increased pro‐inflammatory responses 57,58 . These findings suggest Ninj1 deficiency may contribute to microbial imbalance by increasing basal colonic inflammation due to defective bacterial lysis in macrophages.…”

The Peroxisome Proliferator-Activated Receptor α- Agonist Gemfibrozil Promotes Defense Against Mycobacterium abscessus Infections

“…In addition, the Cxcl5 mRNA level was significantly increased in macrophages and epithelial cells in Sirt3-deficient lung during M. tuberculosis infection [47]. Neutrophil depletion by targeting Ly6G reportedly enhances host defense against M. tuberculosis infection in mice [46][47][48]. In addition, whether CXCL10 is increased in Mabc patients or Mabc infection models is unclear.…”

“…In the lung of Ppara -/mice, Cxcl5 and Cxcl10 expression levels were significantly increased. The chemokine CXCL5 is involved in the regulation of neutrophil influx and pulmonary neutrophil inflammation during M. tuberculosis infection [46][47][48]. In addition, the Cxcl5 mRNA level was significantly increased in macrophages and epithelial cells in Sirt3-deficient lung during M. tuberculosis infection [47].…”

“…The chemokine CXCL5 is involved in the regulation of neutrophil influx and pulmonary neutrophil inflammation during M. tuberculosis infection [46][47][48]. In addition, the Cxcl5 mRNA level was significantly increased in macrophages and epithelial cells in Sirt3-deficient lung during M. tuberculosis infection [47]. Neutrophil depletion by targeting Ly6G reportedly enhances host defense against M. tuberculosis infection in mice [46][47][48].…”

Electrical stimulation inhibits Val-boroPro-induced pyroptosis in THP-1 macrophages via sirtuin3 activation to promote autophagy and inhibit ROS generation

“…Recent research showed that some sirtuin family members, including Sirt1 and Sirt3, can bind and deacetylate ATG5, allowing phagophore elongation and maturation into a double-membrane autophagosome [22,37,38]. To examine if the Sirt3/ATG5 interaction is promoted by ES in our macrophage model of VbPinduced pyroptosis, we first combined MitoTracker staining and immunofluorescence and found that both Sirt3 and ATG5 were predominately expressed in mitochondria ( Supplementary Figure 1).…”