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

Qian-Lu Wang; Lei Yang; Zuo-Liang Liu; Yue Peng; Min Gao; Long-Tian Deng; Xi Liu; Wei Xing

doi:10.1016/j.jcyt.2021.09.001

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. Epub 2021 Dec 14.

Authors

Qian-Lu Wang¹, Lei Yang², Zuo-Liang Liu¹, Yue Peng¹, Min Gao¹, Long-Tian Deng¹, Xi Liu¹, Wei Xing³

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.

PMID: 34920961
DOI: 10.1016/j.jcyt.2021.09.001

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Autophagy
Macrophages
Mice
Respiratory Distress Syndrome* / etiology
Respiratory Distress Syndrome* / therapy
Sepsis* / complications
Sirtuins*

Substances

Sirt6 protein, mouse
Sirtuins