Cardiovascular risk in diabetes remains elevated despite glucose lowering therapies. Given the central role of macrophages in this disease process, we examined whether trained immunity in macrophages could promote persistent pro-atherogenic characteristics. In macrophages, high extracellular glucose promoted pro-inflammatory gene expression and pro-atherogenic functional characteristics, through glycolysis-dependent mechanisms. Bone marrow-derived macrophages (BMDM) from diabetic mice, but cultured in physiological glucose, retained these characteristics, indicating
hyperglycaemic memory
. Bone marrow transplantation from diabetic mice into [normoglycaemic] Ldlr-/- mice increased aortic root atherosclerosis, confirming a disease-relevant form of trained innate immunity. ATAC-seq and RNA-seq analyses of haematopoietic stem cells and BMDM revealed a diabetic
priming effect
that implicated transcription factor,RUNX1. Macrophages laser-captured from human atherosclerotic plaques were also enriched for RUNX1 targets in diabetes, consistent with a potential role in human disease. Innate immune
memory induced by hyperglycaemia may explain why targeting elevated glucose is ineffective in reducing macrovascular risk in diabetes and suggests new targets for disease prevention and therapy.
