Research Paper Volume 12, Issue 10 pp 9534—9548
Dexmedetomidine inhibits LPS-induced proinflammatory responses via suppressing HIF1α-dependent glycolysis in macrophages
- 1 Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai 200433, China
Received: April 15, 2019 Accepted: April 13, 2020 Published: May 20, 2020
https://doi.org/10.18632/aging.103226How to Cite
Copyright © 2020 Meng et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Dexmedetomidine, a highly selective α2-adrenoceptor agonist, has been reported to exert an anti-inflammatory effect in several animal models, but the mechanism remains unclear. Previous studies have shown that hypoxia inducible factor 1α-induced glycolysis is essential for the activation of inflammatory macrophages. However, whether dexmedetomidine influences hypoxia inducible factor 1α-induced glycolysis and thus exerts an anti-inflammatory effect has been poorly investigated. This study aims to elucidate the anti-inflammatory mechanism of dexmedetomidine involving the hypoxia inducible factor 1α-dependent glycolytic pathway. We showed that dexmedetomidine could suppress lipopolysaccharide-induced inflammatory cytokine production; inhibit the extracellular acidification rate, glucose consumption and lactate production; and decrease the expression of glycolytic genes in macrophages. The enhancement of glycolysis by the granulocyte-macrophage colony-stimulating factor or higher concentration of glucose could reverse the anti-inflammatory effect of dexmedetomidine on lipopolysaccharide-treated macrophages. Moreover, dexmedetomidine significantly inhibited the upregulation of hypoxia inducible factor 1α at the mRNA and protein levels. Genetic inhibition of hypoxia inducible factor 1α expression could reverse the anti-inflammatory effect of dexmedetomidine. Taken together, our results indicate that dexmedetomidine attenuates lipopolysaccharide-induced proinflammatory responses partially by suppressing hypoxia inducible factor 1α-dependent glycolysis in macrophages.
Abbreviations
DEX: dexmedetomidine; HIF1α: hypoxia inducible factor 1α; ECAR: extracellular acidification rate; GM-CSF: granulocyte-macrophage colony-stimulating factor; TLRs: toll-like receptors; OXPHOS: oxidative phosphorylation; GLUT1: glucose transporter 1; HK2: Hexokinase-II; PFKFB3: 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase; 2-DG: 2-deoxyglucose; 3PO: 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one; PKM2: pyruvate kinase 2; NLRP3: NOD-, leucine rich region- and pyrin domain-containing-3; AIM2: absent in melanoma 2; HMGB1: high mobility group box 1; mTOR: mammalian target of rapamycin.