Granulocyte-macrophage colony-stimulating factor (GM-CSF) plays a central part in orchestrating trained immunity (TI) across the hematopoietic hierarchy, functioning both as a direct activator of TI and as a critical mediator sustaining TI once established. GM-CSF-induced TI promotes persistent metabolic and epigenetic reprogramming in monocytes and their progenitors, driving long-lasting hyperinflammatory responses that accelerate atherogenesis. In atherosclerotic lesions, elevated GM-CSF amplifies myelopoiesis, enhances monocyte recruitment, and sustains pro-inflammatory macrophage activity, thereby contributing to plaque progression and instability. Because GM-CSF functions both upstream and downstream of TI, it reinforces a self-perpetuating inflammatory circuit within the vessel wall and bone marrow. Targeting GM-CSF or its downstream training pathways therefore offers a promising strategy to interrupt chronic innate immune activation and mitigate cardiovascular risk beyond conventional lipid-lowering therapies. However, the mechanism of GM-CSF-induced TI remains poorly characterized.
In this study, we investigated GM-CSF-induced TI and characterized the accompanying metabolic and epigenetic reprogramming, with a particular focus on the role of liver X receptors (LXRs) in this process. Our results demonstrate that GM-CSF induces TI by enhancing cellular metabolism, as evidenced by increased glycolysis, mitochondrial activity, fatty acid oxidation, and pyruvate metabolism. Lipidomics and RNA sequencing analyses revealed upregulation of lipid synthesis, high triglyceride storage, and acetyl-CoA–producing pathways, leading to increased histone acetylation in GM-CSF–trained cells. Furthermore, glycolysis and mitochondrial metabolism are essential for establishing TI in these cells. Notably, GM-CSF activated LXR signaling, potentially mediated via PPARγ. Pharmacological activation of LXR amplified, but its inhibition attenuated, GM-CSF–induced TI via reducing glycolytic flux and histone acetylation. Interestingly, LXR antagonist suppressed metabolic rewiring and histone modifications induced by oxidized low-density lipoprotein (oxLDL), a pathological LXR agonist.
Together, GM-CSF induced TI may contribute to the pathogenesis of atherosclerosis and cellular metabolism and LXR signaling might be targeted as a potential therapeutic approach to modulate maladaptive TI.
