The inhibition of GLUT1-induced glycolysis in macrophage by phloretin participates in the protection during acute lung injury

Int Immunopharmacol. 2022 Sep:110:109049. doi: 10.1016/j.intimp.2022.109049. Epub 2022 Jul 16.

Abstract

The increased level of glycolysis in macrophage aggravates lipopolysaccharide (LPS)-induced acute lung injury (ALI). Glucose transporter 1 (GLUT1) serves as a ubiquitously expressed glucose transporter, which could activate inflammatory response by mediating glycolysis. Phloretin (PHL), an apple polyphenol, is also an inhibitor of GLUT1, possessing potent anti-inflammatory effects in various diseases. However, the potential role of PHL in ALI remains unclear till now. This study aims to investigate the impacts of PHL on ALI as well as its possible mechanisms. A mouse ALI model was established via intratracheal injection of LPS. LPS-induced primary macrophages were used to mimic in vitro ALI. Mice were pretreated with low or high dosage of PHL for 7 days via intragastric administration once a day before LPS injection. The results showed that PHL pretreatment significantly prevented LPS-induced lung pathological injury and inflammatory response. Meantime, PHL pretreatment also decreased the level of glycolysis in macrophage during ALI. In terms of mechanism, PHL inhibited the mRNA and protein expression of GLUT1. In vitro experiments further showed GLUT1 overexpression in macrophage by infection with lentivirus could abolish the inhibition of inflammation and glycolysis mediated by PHL, suggesting that GLUT1 was essential for the protection of PHL. Taken together, PHL pretreatment may protect against LPS-induced ALI by inhibiting glycolysis in macrophage in a GLUT1-dependent manner, which may be a candidate against ALI in the future.

Keywords: Acute lung injury; GLUT1; Glycolysis; Macrophage; Phloretin.

MeSH terms

  • Acute Lung Injury* / chemically induced
  • Acute Lung Injury* / drug therapy
  • Acute Lung Injury* / metabolism
  • Animals
  • Disease Models, Animal
  • Glucose Transporter Type 1 / genetics
  • Glycolysis
  • Lipopolysaccharides* / pharmacology
  • Lung / pathology
  • Macrophages
  • Mice
  • Mice, Inbred C57BL
  • Phloretin / pharmacology
  • Phloretin / therapeutic use

Substances

  • Glucose Transporter Type 1
  • Lipopolysaccharides
  • Phloretin