Staff Publications

Staff Publications

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    'Staff publications' is the digital repository of Wageningen University & Research

    'Staff publications' contains references to publications authored by Wageningen University staff from 1976 onward.

    Publications authored by the staff of the Research Institutes are available from 1995 onwards.

    Full text documents are added when available. The database is updated daily and currently holds about 240,000 items, of which 72,000 in open access.

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Record number 566431
Title Rewiring of glucose metabolism defines trained immunity induced by oxidized low-density lipoprotein
Author(s) Keating, Samuel T.; Groh, Laszlo; Thiem, Kathrin; Bekkering, Siroon; Li, Yang; Matzaraki, Vasiliki; Heijden, Charlotte D.C.C. van der; Puffelen, Jelmer H. van; Lachmandas, Ekta; Jansen, Trees; Oosting, Marije; Bree, L.C.J. de; Koeken, Valerie A.C.M.; Moorlag, Simone J.C.F.M.; Mourits, Vera P.; Diepen, Janna van; Stienstra, Rinke; Novakovic, Boris; Stunnenberg, Hendrik G.; Crevel, Reinout van; Joosten, Leo A.B.; Netea, Mihai G.; Riksen, Niels P.
Source Journal of Molecular Medicine 98 (2020). - ISSN 0946-2716 - p. 819 - 831.
DOI https://doi.org/10.1007/s00109-020-01915-w
Department(s) Nutrition, Metabolism and Genomics
VLAG
Publication type Refereed Article in a scientific journal
Publication year 2020
Keyword(s) Atherosclerosis - Cardiovascular disease - Diabetes complications - Glycolysis - Immunometabolism - Inflammation - Trained immunity
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.

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