Platelet extracellular vesicles drive monocyte differentiation into inflammatory foam cells in peripheral arterial disease

Inflammatory foam cells (IFC) derived from monocytes drive inflammation within the atherosclerotic plaque. During their differentiation they utilise scavenger receptors to assimilate oxidised low-density lipoproteins (OxLDL), storing the modified protein and lipid cargo in lysosomal storage depots and lipid droplets. The cues supporting their differentiation, and interventions that reverse their inflammatory phenotype are however, poorly understood. Here we show that in age and sex matched healthy donors, CD14⁺ /CD16^- (classical), but not CD14⁺/CD16⁺ (non-classical and intermediate) monocytes form IFC using the CD36 scavenger pathway. The levels of OxLDL assimilation and the ability of IFC to induce secondary leukocyte recruitment to cocultured endothelial cells corelated closely with CD36 expression and OxLDL load. However, in patients with advanced peripheral arterial disease all monocyte subsets formed IFC. Efficient differentiation into IFC required priming of the monocytes by platelet extracellular vesicles (PEV), and using patient PEV to prime monocytes from healthy donors resulted in IFC formation in all monocyte subsets, implying that differential responses in healthy and patient monocytes was dependent upon the cargo conveyed by PEV. The IFC from healthy donors but not from PAD patients were sensitive to the n3-PUFA, eicosapentaenoic acid (EPA), which promoted clearance of depots of OxLDL derived cargo, including the disposal of lipid droplets through increased β-oxidation. Thus, intake of n3-PUFAs during a healthy life span may reduce arterial inflammation driven by IFC, however, upon acquisition of established and serious atherosclerosis, supplementation with n3-PUFAs must intervene in the disease process by alternative mechanisms.