Extracellular Vesicle Eicosanoids Mediate Monocyte Migration

BACKGROUND: Extracellular vesicles (EVs) moderate a variety of physiological and pathological processes by enabling the intercellular transfer of proteins, nucleic acids, and lipids. Bioactive lipids such as polyunsaturated fatty acids or eicosanoids play an important role in propagation and resolution of inflammation and in vascular regulation. We previously found that the lipid composition of macrophage-derived EVs depends on polarization of the originating macrophages. METHODS: In this study, we investigated the role of EV-contained 12-LOX (12-lipoxygenase) metabolites in the moderation of inflammation. We used in vitro functional cell culture models as well as an in vivo sterile peritonitis model with male wild-type mice. RESULTS: We found increased levels of these 12-LOX products in M1 macrophages and M1 macrophage-derived EVs. Inhibition of 12-LOX led to significantly lower levels of 12-LOX metabolites in M1 EVs and attenuated M1 EV-mediated proinflammatory effects such as production of MCP-1 (monocyte chemoattractant protein 1) and CXCL10 (C-X-C motif chemokine ligand 10). M1 EVs induced monocyte adhesion and migration, which were also reduced by 12-LOX inhibition. In a sterile peritonitis model, M1 EVs increased the migration of monocytes into the peritoneum and the presence of macrophages in the peritoneal wall. Both effects were diminished by 12-LOX inhibition. CONCLUSIONS: Our results show that the specific lipid profile in macrophage-derived EVs is functionally relevant during inflammation. We demonstrate that eicosanoids in M1 macrophage-derived EVs educate other cells towards a proinflammatory phenotype, promoting inflammation and endothelial dysfunction.