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

Samuel T. Keating, Laszlo Groh, Kathrin Thiem, Siroon Bekkering, Yang Li, Vasiliki Matzaraki, Charlotte D.C.C. van der Heijden, Jelmer H. van Puffelen, Ekta Lachmandas, Trees Jansen, Marije Oosting, L.C.J. de Bree, Valerie A.C.M. Koeken, Simone J.C.F.M. Moorlag, Vera P. Mourits, Janna van Diepen, Rinke Stienstra, Boris Novakovic, Hendrik G. Stunnenberg, Reinout van CrevelLeo A.B. Joosten, Mihai G. Netea, Niels P. Riksen*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

10 Citations (Scopus)

Abstract

Abstract: 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.

Original languageEnglish
Pages (from-to)819-831
JournalJournal of Molecular Medicine
Volume98
DOIs
Publication statusPublished - 30 Apr 2020

Keywords

  • Atherosclerosis
  • Cardiovascular disease
  • Diabetes complications
  • Glycolysis
  • Immunometabolism
  • Inflammation
  • Trained immunity

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