Lipidome profiling of human and equine neutrophil-derived extracellular vesicles and their potential contribution to the ensemble of synovial fluid-derived extracellular vesicles during joint inflammation
The molecular signature of cell-derived extracellular vesicles (EVs) in synovial fluid (SF) can provide information about cells and molecular processes involved in joint disorders. The EV signature and function are determined by cargo molecules and the lesser-studied membrane lipid bilayer. We here investigated how inflammatory stimuli alter the lipidomic profile of human and equine neutrophil-derived EVs (nEVs) in vitro and how the inflammatory response aligns the lipidomic profile of SF-EVs from inflamed joints. Hereto, the lipidomic profiles of SF-EVs from Rheumatoid Arthritis (RA) and Spondyloarthritis (SpA) patients, two autoimmune-driven joint diseases, and equine SF-EVs from induced acute synovitis were used for comparison. We identified neutrophil stimulation dependent changes in the lipidomic profile of nEVs with elevated presence of dihexosylceramide (lactosylceramide), phosphatidylserine and phosphatidylethanolamine ether-linked lipid classes in human nEVs upon full activation. In horses, levels of monohexosylceramide (glucosylceramide) increased instead of dihexosylceramide, indicating species-specific differences. The lipid profiles of RA and SpA SF-EVs were relatively similar and showed resemblance with human nEVs. Similarly, the lipidome of equine synovitis-derived SF-EVs resembled the one of equine nEVs. Hence, lipidome profiling can provide insights into the contribution of nEVs to the heterogeneous pool of SF-EVs, deepening our understanding of inflammatory joint diseases and revealing molecular changes in joint homeostasis.
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