Dexmedetomidine Activates Akt, STAT6 and IRF4 Modulating Cytoprotection and Macrophage Anti-Inflammatory Phenotype Against Acute Lung Injury in vivo and in vitro

Qian Chen; Zhigang Qin; Yibing Sun; Xiangfeng Liu; Aurelie Pac Soo; Enqiang Chang; Qizhe Sun; Bin Yi; Dong-Xin Wang; Hailin Zhao; Daqing Ma; Jianteng Gu

doi:10.2147/JIR.S357012

Dexmedetomidine Activates Akt, STAT6 and IRF4 Modulating Cytoprotection and Macrophage Anti-Inflammatory Phenotype Against Acute Lung Injury in vivo and in vitro

J Inflamm Res. 2022 Apr 26:15:2707-2720. doi: 10.2147/JIR.S357012. eCollection 2022.

Authors

Qian Chen^#^{1

2}, Zhigang Qin^#¹, Yibing Sun³, Xiangfeng Liu¹, Aurelie Pac Soo², Enqiang Chang², Qizhe Sun², Bin Yi¹, Dong-Xin Wang³, Hailin Zhao², Daqing Ma², Jianteng Gu¹

Affiliations

¹ Department of Anaesthesiology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, People's Republic of China.
² Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea & Westminster Hospital, London, UK.
³ Department of Anaesthesiology and Critical Care Medicine, Peking University First Hospital, Beijing, People's Republic of China.

^# Contributed equally.

Abstract

Purpose: This study aims to investigate the cytoprotective and anti-inflammatory effects of an α₂-adrenoreceptor (α₂-AR) agonist, dexmedetomidine (Dex), on lipopolysaccharides (LPS)-induced acute lung injury and underlying mechanisms with focus on alveolar macrophage polarization modulation.

Methods: C57BL/6 mice were intraperitoneally injected LPS (10 mg/kg) with or without Dex (25 µg/kg) and/or α₂-AR antagonist atipamezole (Atip, 500 µg/kg). Lung tissues were then analysed to determine injuries. In vitro, human pulmonary epithelial cells (A549) and mice alveolar macrophages (MH-S) were exposed to LPS (10 ng/mL) with or without different concentrations of Dex (0.1-100 nM). Alveolar macrophage polarization, NLRP3 inflammasome activation and inflammatory responses were determined. PTEN/Akt signaling and its downstream transcriptional factors as targets for macrophage polarization were assessed.

Results: Dex treatment significantly reduced pro-inflammatory M1 macrophage polarization and NLRP3 inflammasome activation in the lungs relative to the mice treated with LPS. The similar pattern reduction of NLRP3 inflammasome activation by Dex was also found in A549 cells. Atip partly reversed the anti-inflammatory effects of Dex. In cultured alveolar macrophages, Dex reduced LPS-mediated expression of IL-1, -6 and TNF-α receptors while promoting alveolar macrophages differentiation towards a M2 anti-inflammatory phenotype. Additionally, LPS increased Akt signaling activation in a time-dependent manner, which was further activated by Dex via inhibiting phosphatase and tensin homolog (PTEN). The action of Dex on Akt signaling shifted alveolar macrophages from M1 to M2 phenotype through increasing STAT6 and IRF4 transcriptional factors.

Conclusion: Dex protected against LPS-induced lung injury and suppressed LPS-induced pulmonary inflammatory responses by attenuating the NLRP3 inflammasome activation and promoting anti-inflammatory M2 macrophage polarization.

Keywords: Akt signaling; acute lung injury; dexmedetomidine; macrophage polarization; sepsis.

Grants and funding

This work was supported by the National Natural Science Foundation of China (No. 81772050, 81801900), The Basic and Frontier Research Fund of Chongqing, China (No. cstc2018jcyjAX0007, cstc2018jcyjAX0577), Excellent Talents Foundation of Army Medical University (XZ2019-505-028), Chongqing, China, The British Medical Research Council, The Chelsea-Westminster Hospital Joint Research Committee Grant and BJA/RCoA project grant, London, UK.