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. Charlotte J. de Bree, Valerie A. C. M. Koeken, Simone J. C. F. M. Moorlag, Vera P. Mourits, Janna van Diepen, Rinke Strienstra, 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

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    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
    Number of pages13
    JournalJournal of Molecular Medicine
    Issue number6
    Publication statusPublished - Jun-2020


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

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