2016 ATVB Plenary Lecture

Receptor for advanced glycation endproducts (RAGE) and monocyte/macrophage perturbation. The unique cadre of RAGE ligands, via RAGE, stimulates key perturbations in monocytes/macrophages, such as induction of oxidative stress and consequent activation of nuclear factor (NF)-κB; migration (at least in response to RAGE ligand-mediated upregulation of adhesion molecules and chemokines on endothelial cells); downregulation of cholesterol transporters ABCG1 (ATP-binding cassette sub-family G member 1) and ABCA1 (ATP-binding cassette sub-family A member 1), leading to suppression of cholesterol efflux; and downregulation of PPARG and other mediators that tip the balance to increased expression of proinflammatory vs reduced expression of anti-inflammatory mediators, thereby contributing to sustained inflammation and tissue damage. These facets of RAGE pathobiology in macrophages have implications for atherosclerosis and diet-induced obesity, as well as for chronic inflammatory disorders. More study needs to be done to determine whether RAGE modulates glucose/fatty acid metabolism in these cells and whether such effects might affect macrophage properties in responses to stress. Findings to date suggest that targeting RAGE may be beneficial in chronic immunometabolic disorders and that biomarking RAGE activity in circulating monocytes/monocyte-derived macrophages may be a key strategy to track target engagement for future clinical trials. HDL indicates high-density lipoprotein; ICAM1, intercellular adhesion molecule 1; MCP1, monocyte chemotactic protein 1; PPARγ, peroxisome proliferator-activated receptor gamma; ROS, reactive oxygen species; and VCAM1, vascular cell adhesion molecule 1.