Rewiring of glucose metabolism defines trained immunity induced by oxidized low-density lipoprotein
SourceJournal of Molecular Medicine-Jmm, 98, 6, (2020), pp. 819-831
Article / Letter to editor
Display more detailsDisplay less details
Journal of Molecular Medicine-Jmm
SubjectMolecular Biology; Radboudumc 15: Urological cancers RIHS: Radboud Institute for Health Sciences; Radboudumc 16: Vascular damage RIMLS: Radboud Institute for Molecular Life Sciences; Radboudumc 4: lnfectious Diseases and Global Health RIHS: Radboud Institute for Health Sciences; Radboudumc 4: lnfectious Diseases and Global Health RIMLS: Radboud Institute for Molecular Life Sciences; Radboudumc 6: Metabolic Disorders RIMLS: Radboud Institute for Molecular Life Sciences
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.
Upload full text
Use your RU credentials (u/z-number and password) to log in with SURFconext to upload a file for processing by the repository team.