Coordinate stimulation of macrophages by microparticles and TLR ligands promotes foam cell formation (116.9)

Abstract

Abstract Macrophage dysregulation through the uptake of and signaling by oxidized lipoproteins can lead to atherosclerosis. Recent evidence shows that Toll-like Receptor signaling plays an emerging role in the onset of atherosclerosis by increasing foam cell formation. To investigate the link between TLR signaling and foam cell formation, we established an in vitro assay utilizing liposomes of defined lipid compositions. We found that TLRs signaling through Trif promoted foam cell formation by inducing Type I IFN production, whereas TLRs that do not induce IFN, like TLR2, did not enhance foam cell formation. However, in combination with IFNα, TLR2 did promote robust foam cell formation. We then investigated the ability of microparticles to also contribute to foam cell formation. We found that both exosomes and ectosomes promoted foam cell formation and macrophage activation, and was enhanced by TLR stimulation or IFNα. To dissect the temporal kinetics, we sequentially added microparticles and LPS. We found that activation of the macrophages with LPS prior to microparticle treatment, but not vice versa, led to enhanced foam cell formation, suggesting that previously activated macrophages are more prone to foam cell formation. Finally, microparticles stimulated foam cell formation in a tissue model. Taken together, these data suggest that foam cell formation can be triggered by microparticles in the context of TLR stimulation.