Rewiring of glucose metabolism defines trained immunity induced by oxidized low-density lipoprotein

J Mol Med (Berl). 2020 Jun;98(6):819-831. doi: 10.1007/s00109-020-01915-w. Epub 2020 Apr 30.


Stimulation of monocytes with microbial and non-microbial products, including oxidized low-density lipoprotein (oxLDL), induces a protracted pro-inflammatory, atherogenic phenotype sustained by metabolic and epigenetic reprogramming via a process called trained immunity. We investigated the intracellular metabolic mechanisms driving oxLDL-induced trained immunity in human primary monocytes and observed concomitant upregulation of glycolytic activity and oxygen consumption. In two separate cohorts of healthy volunteers, we assessed the impact of genetic variation in glycolytic genes on the training capacity of monocytes and found that variants mapped to glycolytic enzymes PFKFB3 and PFKP influenced trained immunity by oxLDL. Subsequent functional validation with inhibitors of glycolytic metabolism revealed dose-dependent inhibition of trained immunity in vitro. Furthermore, in vivo administration of the glucose metabolism modulator metformin abrogated the ability for human monocytes to mount a trained response to oxLDL. These findings underscore the importance of cellular metabolism for oxLDL-induced trained immunity and highlight potential immunomodulatory strategies for clinical management of atherosclerosis. KEY MESSAGES: Brief stimulation of monocytes to oxLDL induces a prolonged inflammatory phenotype. This is due to upregulation of glycolytic metabolism. Genetic variation in glycolytic genes modulates oxLDL-induced trained immunity. Pharmacological inhibition of glycolysis prevents trained immunity.

Keywords: Atherosclerosis; Cardiovascular disease; Diabetes complications; Glycolysis; Immunometabolism; Inflammation; Trained immunity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptive Immunity* / drug effects
  • Adaptive Immunity* / genetics
  • Blood Glucose
  • Cytokines / metabolism
  • Energy Metabolism* / drug effects
  • Energy Metabolism* / genetics
  • Gene Expression Regulation, Enzymologic
  • Genetic Variation
  • Glucose / metabolism*
  • Glycolysis / genetics
  • Humans
  • Immunomodulation*
  • Inflammation Mediators / metabolism
  • Leukocytes, Mononuclear / immunology
  • Leukocytes, Mononuclear / metabolism
  • Lipoproteins, LDL / metabolism*
  • Metformin / pharmacology
  • Quantitative Trait Loci
  • Quantitative Trait, Heritable


  • Blood Glucose
  • Cytokines
  • Inflammation Mediators
  • Lipoproteins, LDL
  • oxidized low density lipoprotein
  • Metformin
  • Glucose