Abstract 148: AGES, Receptor for Advanced Glycation End Products (RAGE), Reverse Transmigration of Macrophages & Polarization

Cellular migration is fundamental processes linked to diverse pathological states including atherosclerosis and diabetes. RAGE is a multiligand cell surface macromolecule, which binds ligands such as advanced glycation endproducts (AGEs) in diseased settings such as atherosclerosis. We tested the hypothesis that RAGE contributes to impaired regression of diabetic atherosclerosis by suppression of reverse transmigration of macrophages in an AGE-enriched environment. We performed our studies in vitro, a reverse transmigration assay, using primary murine aortic endothelial cells from wild-type C57BL6 mice and wild-type or RAGE deficient primary bone marrow derived macrophages (BMDMs). Our data is shown in the table. We evaluate if the expression of RAGE modulates influx and/or egress of macrophages from the atherosclerotic lesions in the non-diabetic and diabetic states. We used a monocyte bead-tracking model in an aorta transplantation study with LDL-/-diabetic mice fed high-fat diet as a baseline (donors), and non-diabetic RAGE-/- or WT mice as recipient. Migration patterns evaluated by labeled monocytes, showed a decrease in bead number in RKO recipients (23±0.05 p<0.05) compared to WT (30±0.05 p<0.05) indicating emigration of monocyte- derived cells from the plaque in the diabetic state. We also tested if RAGE plays roles in macrophage polarization. AGEs-RAGE axis increases M1 polarization (MCP 1, TNF alpha, iNos, p<0.05) and suppresses M2 polarization (Arg1, IL-10, p<0.05) in a manner prevented by deletion of RAGE in BMDMs. Our studies suggest AGEs-RAGE axis action delays reverse transmigration of macrophages and augments pro-inflammatory gene expression.