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  • Synergy between 15-lipoxygenase and secreted ▫$PLA_2$▫ promotes inflammation by formation of TLR4 agonists from extracellular vesicles [Elektronski vir]
    Ha, Van Thai ...
    Damage-associated endogenous molecules induce innate immune response, thus making sterile inflammation medically relevant. Stress-derived extracellular vesicles (stressEVs) released during oxidative ... stress conditions were previously found to activate Toll-like receptor 4 (TLR4), resulting in expression of a different pattern of immune response proteins in comparison to lipopolysaccharide (LPS), underlying the differences between pathogen-induced and sterile inflammation. Here we report that synergistic activities of 15-lipoxygenase (15-LO) and secreted phospholipase A2 (sPLA2) are needed for the formation of TLR4 agonists, which were identified as lysophospholipids (lysoPLs) with oxidized unsaturated acyl chain. Hydroxy, hydroperoxy, and keto products of 2-arachidonoyl-lysoPI oxidation by 15-LO were identified by mass spectrometry (MS), and they activated the same gene pattern as stressEVs. Extracellular PLA2 activity was detected in the synovial fluid from rheumatoid arthritis and gout patients. Furthermore, injection of sPLA2 promoted K/BxN serum-induced arthritis in mice, whereby ankle swelling was partially TLR4 dependent. Results confirm the role of oxidized lysoPL of stressEVs in sterile inflammation that promotes chronic diseases. Both 15-LO and sPLA2 enzymes are induced during inflammation, which opens the opportunity for therapy without compromising innate immunity against pathogens.
    Vir: Proceedings of the National Academy of Sciences of the United States of America [Elektronski vir]. - ISSN 1091-6490 (Vol. 117, iss. 41, 13 Oct. 2020, str. 25679-25689)
    Vrsta gradiva - e-članek
    Leto - 2020
    Jezik - angleški
    COBISS.SI-ID - 30457091

    Povezava(-e):

    https://www.pnas.org/content/early/2020/09/23/2005111117
    DOI

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