The role of extracellular vesicles snd their synthetic analogues in the modulation of TLR4 activityHa, Van Thai (Avtor)
ManĨek Keber, Mateja (Mentor)
Immunology/ sterile inflammation/ TLR4/ extracellular vesicles/ oxidized phospholipid/ 15-lipoxygenase/ secreted phospholipase A2During oxidative stress conditions, endogenous stress-derived EVs (stressEVs) were found to activate Toll-like receptor 4 (TLR4) with a gene profile different from lipopolysaccharide (LPS). Here we show that stressEVs in comparison to LPS activate several different transcription factors resulting in activation of different immune response genes underlying the differences between pathogen-induced and sterile inflammation. Additionally, concerted activity of 15-lipoxygenase (15-LO) and secretory phospholipase A2 (sPLA2) is needed for the formation of TLR4 agonists, which we identified as lysophospholipids (lysoPLs) with oxidized unsaturated fatty acid. Hydroxy, hydroperoxy and keto products of 20:4 lysoPI were determined by mass spectrometry and they activated the same gene pattern as stressEVs. Furthermore, sPLA2 activity in the synovial fluid from rheumatoid arthritis patients promoted formation of the TLR4 agonists. Injection of sPLA2 promoted K/BxN serum induced arthritis in mice and swelling of the ankles was partially TLR4-dependent. Because both enzymes are induced during inflammation, these results confirm the role of stressEVs in sterile inflammation that promotes chronic diseases and opens the opportunity to treat diseases without affecting systemic innate immunity.20202020-11-26 07:15:11Doktorsko delo/naloga122145VisID: 16280COBISS_ID: 56449027sl