Abstract 217: LOX-1 Primarily Contributes to M1 Macrophage Induced Foam Cell Formation

Objectives: Modified LDL uptake by macrophages (MΦ) leading to foam cell formation is an early event in atherosclerosis. Recent studies suggest that MΦ polarization contributes to the progression of atherosclerosis. Therefore, we investigated the hypothesis that macrophage plasticity affects modified LDL uptake and subsequent foam cell formation. Approach & Results: Bone marrow-derived MΦ were treated with LPS and IFNγ or IL-4 to induce MΦ polarization to M(LPS/IFNγ or M1) and M (IL4 or M2) phenotypes. Foam cell formation was determined after incubating M(LPS/IFNγ) and M(IL4) MΦ with oxidized-LDL. Our results show that formation of foam cells was marginally increased in M(IL4) MΦ compared to un-polarized M(-) MΦ. However, accumulation of neutral lipids was higher in M(LPS/IFNγ) MΦ compared to M(IL4) MΦ indicating that foam cell formation is enhanced by polarization to pro-inflammatory M(LPS/IFNγ) MΦ. Interestingly, mRNA and protein expression of CD36, one of the major scavenger receptors, were lower in M(LPS/IFNγ) MΦ compared to un-polarized MΦ. To assess the specific contribution of CD36, foam cell formation was assessed in MΦ isolated from CD36-deficient mice. Notably, oxidized-LDL uptake and foam cell formation in CD36-deficient M(LPS/IFNγ) MΦ was similar to M(LPS/IFNγ) MΦ from wild type mice. This indicates that CD36 does not mediate the increased foam cell formation in M(LPS/IFNγ) MΦ. We therefore examined expression of LOX-1, another scavenger receptor implicated in foam cell formation. We found that both mRNA and protein expression for LOX-1 increased several fold in M(LPS/IFNγ) MΦ. We also showed that TLR4-mediated NF-κB activation is the primary mechanism for the increased LOX-1 expression and foam cell formation in M(LPS/IFNγ) polarized MΦ. Conclusion: Macrophage plasticity, specifically polarization of MΦ to pro-inflammatory M(LPS/IFNγ) phenotype promotes foam cell formation, which has implications for the progression of atherosclerosis.