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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Highlights d Set7 regulates enhanced cytokine production in trained immunity in vitro d Set7 knockout mice are unable to mount trained immunity against endotoxin challenge d Set7 modulates cellular respiration in b-glucan-trained macrophages d Set7-dependent histone methylation regulates MDH2 and SDHB in trained cells

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