Inhibition of Aerobic Glycolysis Promotes Neutrophil to Influx to the Infectious Site Via CXCR2 in Sepsis. Issue 1 (January 2020)

• Record Type: Journal Article
• Authors: Tan, Chuyi; Gu, Jia; Chen, Huan; Li, Tao; Deng, Huafei; Liu, Ke; Liu, Meidong; Tan, Sipin; Xiao, Zihui; Zhang, Huali; Xiao, Xianzhong
• Is Part Of: Shock. Volume 53:Issue 1(2020)
• Publication Date: 2020-01
• Subjects: 2-deoxyglucose -- G protein-coupled receptor kinase-2 -- immune metabolism -- mice -- Abbreviations -- 2-DG -- 2-deoxyglucose -- ALT -- alanine aminotransferase -- AST -- aspartate aminotransferase -- CLP -- cecal ligation and puncture -- CXCR2 -- chemokine receptor 2 -- DMSO -- dimethylsulfoxide -- ERK -- extracellular regulated protein kinases -- GRK2 -- G protein-coupled receptor kinase-2 -- HIF1A -- hypoxia inducible factor 1 subunit alpha -- IL-1β -- interleukin-1β -- IL-6 -- interleukin-6 -- LDHA -- lactate dehydrogenase subunit alpha -- LPS -- lipopolysaccharides -- NETs -- neutrophil extracellular traps -- PKM2 -- pyruvate kinase M2 -- ROS -- reactive oxygen species -- Scr -- serum creatinine -- TNF-α -- tumor necrosis factor-α; Shock -- Periodicals; Shock -- Periodicals; Choc (Pathologie) -- Périodiques; Shock; Periodicals; 616.0475
• DOI: 10.1097/SHK.0000000000001334
• Languages: English
• ISSNs: 1073-2322

Abstract

Abstract : ABSTRACT: Recent evidences suggest that metabolic reprogramming plays an important role in the regulation of innate inflammatory response; however, the specific mechanism is unclear. In this study, we found that glycolytic inhibitor 2-deoxyglucose (2-DG) significantly improved the survival rate in cecal ligation and puncture (CLP)-induced septic mice. 2-DG-treated mice developed increased neutrophil migration to the infectious site and more efficient bacterial clearance than untreated mice. 2-DG reversed the down-regulation of chemokine receptor 2 (CXCR2) and the impaired chemotaxis induced by CLP in mice or lipopolysaccharides (LPS) in human neutrophils. Furthermore, 2-DG reversed the down-regulation of CXCR2 in neutrophils by decreasing the expression of G protein-coupled receptor kinase-2 (GRK2), a serin-threonine protein kinase that mediated the internalization of chemokine receptors, which was induced via the inhibition of extracellular regulated protein kinases (ERK) phosphorylation and the promotion of P38 phosphorylation. Finally, SB225002, a CXCR2 antagonist, partially blocked the protective effects of 2-DG in sepsis. Together, we found a novel mechanism for the migration of neutrophils regulated by metabolism and suggested that aerobic glycolysis might be a potential target of intervention in sepsis. Abstract : Supplemental Digital Content is available in the text