175 - LOS-1 Primarily Contributes to Pro-Inflammatory Macrophages Induced Foam Cell Formation

Abstract

Modified LDL uptake by macrophages lead to formation of foam cells is an early event in atherosclerosis. Recent studies have suggested that macrophage polarization contributes to the progression of atherosclerosis. In this report, we investigated the hypothesis that macrophage polarization differentially affects modified LDL uptake and subsequent foam cell formation. Bone marrow-derived macrophages (BMDM) were exposed to LPS and IFNγ or IL-4 to induce M1 and M2 macrophage polarization. The formation of foam cells was assessed after exposing M1 and M2 macrophages to oxidized-LDL. Our results show that formation of foam cells was slightly increased in M2 macrophages. Interestingly, accumulation of neutral lipids was high in M1 macrophages indicating M1 polarization promotes foam cells. In M1 macrophages, mRNA and protein expression of scavenger receptor CD36 was lower compared to unpolarized macrophages. Notably, mRNA and protein expression of LOX-1 were increased several fold in M1 macrophages. M2 polarized BMDM from CD36 knock out or scavenger receptor-A (SR-A) knockout mice showed reduced foam cells. Surprisingly, M1 polarized macrophages from CD36 or SR-A knockout mice showed similar levels of foam cells compared to M1 polarized macrophages from wild type mice. These results suggest that CD36 and SR-A do not contribute to increased foam cells in M1 macrophages. Further studies also reveal that NF-kB activation through TLR4 is the major contributor for increased LOX1-expression and foam cell formation in M1 polarized macrophages. Macrophage plasticity, specifically polarization of macrophages to pro-inflammatory M1 phenotype promotes foam cell formation through LOX-1, which has implications for the progression of atherosclerotic plaques.