Page 30 - M. Immunology

[M. Immunology-21]

Sirtuin 3 activation enhances autophagy and antimicrobial

responses and ameliorates mitochondrial damage and

oxidative stress during Mtb infection

Tae Sung Kim¹˙²˙³, Hyun-Woo Suh¹˙²˙³, Eun-Kyeong Jo¹˙²˙³˙*, Jin Kyung Kim¹˙²˙³, Jin Ho Choe¹˙²˙³, Young Jae Kim¹˙²˙³,

Chaeuk Chung⁴, Jin-Man Kim⁵

¹Department of Microbiology, Chungnam National University School of Medicine, Daejeon 35015, Korea, ²Department of

Medical Science, Chungnam National University School of Medicine, Daejeon 35015, Korea, ³Infection Control
Convergence Research Center, Chungnam National University, Daejeon 35015, Korea, ⁴Division of Pulmonary and Critical
Care, Chungnam National University School of Medicine, Daejeon 35015, Korea, ⁵Department of Pathology, Chungnam

National University School of Medicine, Daejeon 35015, Korea

Sirtuin 3 (SIRT3), a mitochondrial NAD+-dependent deacetylase belonging to class III histone deacetylases, is

essential for orchestrating mitochondrial energy metabolism and homeostasis. However, it is largely unknown the
specific role of SIRT3 in the regulation of the innate host defense during mycobacterial infection. In this study, using

a biphenolic compound honokiol (HKL), a specific SIRT3 activator, we showed that SIRT3 activation by HKL enhanced
autophagy, autophagic flux, and antimicrobial effects in macrophages. Stimulation of bone marrow-derived

macrophages (BMDMs) with HKL significantly increased the formation of autophagy, which was significantly lower
in sirt3-/- BMDMs. In addition, HKL treatment dramatically inhibited mitochondrial ROS generation and intracellular

Mycobacterium tuberculosis survival during infection. However, these effects were sharply abolished in sirt3-/-
BMDMs. Furthermore, we found that SIRT3 and PPARA levels were lower, whereas levels of inflammatory cytokines
TNF, IL1B, and IL6 were higher, in peripheral immune cells from tuberculosis patients. These data suggest the clinical

relevance of SIRT3 and PPARA levels in human tuberculosis. In addition, these data demonstrate a function of SIRT3

in the anti-mycobacterial host defense through coordin