1. Academic Validation
  2. Sirtuin 6 regulates macrophage polarization to alleviate sepsis-induced acute respiratory distress syndrome via dual mechanisms dependent on and independent of autophagy

Sirtuin 6 regulates macrophage polarization to alleviate sepsis-induced acute respiratory distress syndrome via dual mechanisms dependent on and independent of autophagy

  • Cytotherapy. 2022 Feb;24(2):149-160. doi: 10.1016/j.jcyt.2021.09.001.
Qian-Lu Wang 1 Lei Yang 2 Zuo-Liang Liu 1 Yue Peng 1 Min Gao 1 Long-Tian Deng 1 Xi Liu 1 Wei Xing 3
Affiliations

Affiliations

  • 1 Department of Intensive Care Medicine, The Third Xiangya Hospital of Central South University, Changsha, China.
  • 2 Department of Preparations, The First Hospital of Hunan University of Chinese Medicine, Changsha, China.
  • 3 Department of Intensive Care Medicine, The Third Xiangya Hospital of Central South University, Changsha, China. Electronic address: xy3yyxw@csu.edu.cn.
Abstract

Background aims: Sepsis-induced acute respiratory distress syndrome (ARDS) can be mediated by an imbalance in macrophage polarization; however, the underlying mechanisms remain poorly understood. This study aimed to investigate the modulatory role of Sirtuin 6 (SIRT6) in macrophage polarization during sepsis-induced ARDS.

Methods: A mouse ARDS model was established using cecal ligation and puncture. Isolated alveolar macrophages (AMs) and lipopolysaccharide (LPS)-stimulated bone marrow-derived macrophages (BMDMs) were adopted as in vitro models. Macrophage polarization was evaluated by measuring M1 and M2 macrophage percentages via flow cytometry and expression of specific markers. The expression of microtubule-associated LIGHT chain protein 3I/II and beclin-1 was detected for assessing macrophage Autophagy. Binding between specificity protein 1 (SP1) and the target gene promoter was evaluated using a chromatin immunoprecipitation assay. RNA expression was analyzed by quantitative reverse transcription polymerase chain reaction and western blotting.

Results: Treatment with the SIRT6 Activator UBCS039 significantly alleviated lung injury in the mouse ARDS model and enhanced Autophagy and M2 polarization in isolated AMs. M2 polarization and Autophagy in LPS-challenged BMDMs were also effectively promoted by UBCS039 treatment or SIRT6 overexpression. An adenosine monophosphate-activated protein kinase inhibitor (Compound C) or Autophagy Inhibitor (3-methyladenine) partially abrogated M2 polarization mediated by SIRT6 overexpression upon LPS exposure. SIRT6 induced Autophagy and M2 polarization of BMDMs partially via its deacetylase activity. SIRT6 inhibited mammalian target of rapamycin transcription by modulating SP1 to promote BMDM M2 polarization, which was independent of Autophagy.

Conclusions: SIRT6 promotes M2 polarization of macrophages to alleviate sepsis-induced ARDS in an autophagy-dependent and -independent manner.

Keywords

SIRT6; acute lung injury; autophagy; macrophage polarization; sepsis-induced ARDS.

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