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

Authors
  • Keating, Samuel T.1
  • Groh, Laszlo1
  • Thiem, Kathrin1
  • Bekkering, Siroon1
  • Li, Yang2
  • Matzaraki, Vasiliki1, 2
  • van der Heijden, Charlotte D. C. C.1
  • van Puffelen, Jelmer H.1, 3
  • Lachmandas, Ekta1
  • Jansen, Trees1
  • Oosting, Marije1
  • de Bree, L. Charlotte J.1, 4, 5
  • Koeken, Valerie A. C. M.1
  • Moorlag, Simone J. C. F. M.1
  • Mourits, Vera P.1
  • van Diepen, Janna1
  • Strienstra, Rinke1, 6
  • Novakovic, Boris7, 8
  • Stunnenberg, Hendrik G.7
  • van Crevel, Reinout1
  • And 3 more
  • 1 Radboud University Medical Center, Nijmegen, 6500 HB, the Netherlands , Nijmegen (Netherlands)
  • 2 University Medical Center Groningen, Groningen, the Netherlands , Groningen (Netherlands)
  • 3 Radboud University Medical Center, Nijmegen, the Netherlands , Nijmegen (Netherlands)
  • 4 Statens Serum Institut, Copenhagen, Denmark , Copenhagen (Denmark)
  • 5 University of Southern Denmark/Odense University Hospital, Odense, Denmark , Odense (Denmark)
  • 6 Wageningen University, Wageningen, 6700 AA, the Netherlands , Wageningen (Netherlands)
  • 7 Radboud University, Nijmegen, 6525 GA, the Netherlands , Nijmegen (Netherlands)
  • 8 University of Melbourne, Parkville, VIC, 3052, Australia , Parkville (Australia)
  • 9 Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania , Cluj-Napoca (Romania)
  • 10 University of Bonn, Bonn, 53115, Germany , Bonn (Germany)
Type
Published Article
Journal
Journal of Molecular Medicine
Publisher
Springer-Verlag
Publication Date
Apr 30, 2020
Volume
98
Issue
6
Pages
819–831
Identifiers
DOI: 10.1007/s00109-020-01915-w
Source
Springer Nature
Keywords
License
Green

Abstract

AbstractStimulation 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 messagesBrief 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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