Trained immunity in hyperuricemia and gout: Targeting epigenetic marks to reduce cardiovascular risk

While the link between hyperuricemia (HU) and gout with major adverse cardiovascular events (MACE) is well established, the underlying mechanism remains poorly understood. Here, we propose that this mechanism is rooted in trained innate immunity in myeloid cells as well as vascular endothelial cells. Soluble urate is a low-grade damage associated molecular pattern (DAMP) similar to already established stimuli that induce trained immunity and thereby establishes persistent epigenetic pro-inflammatory histone modifications (H3K4me1, H3K4me3, H3K27ac) increasing chromatin accessibility at particular gene regions. In addition, we suggest this is further amplified during acute gout flares through systemic IL-1β release that introduces the changes within the hematopoietic stem and progenitor cells (HSPCs). The HSPCs reprogramming leads to increased myelopoiesis which results in hyper-reactive myeloid cells. Together with the primed vasculature, we hypothesize that maladaptive epigenetic rewiring is the core mechanism that links HU and gout to MACE upon an additional secondary metabolic stressor. Hence, we introduce a three-pillar model (1. local priming, 2. Central amplification, 3. Peripheral acceleration) that captures the spatiotemporal axis of this process. While classic gout treatments manage symptoms, they leave the epigenetic landscape untouched. We therefore discuss epidrugs and cell-specific nanomedicine deliveries as compelling strategies to reverse the maladaptive epigenetic scars to reduce long-term MACE risk in these patients.