Synergy between 15-lipoxygenase and secreted PLA ₂ promotes inflammation by formation of TLR4 agonists from extracellular vesicles

Abstract

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.

Role of Arachidonic Acid and Its Metabolites in the Biological and Clinical Manifestations of Idiopathic Nephrotic Syndrome

“…Infections activate the immune system, triggering the inflammatory cascade. It was recently reported that during inflammation two enzymes are induced: 15-lipoxygenase (15-LO) and secreted phospholipase A 2 (sPLA 2 ) [ 58 ]. Notably, 15-LO is expressed in human podocytes [ 59 ], while sPLA 2 is expressed in platelets, neutrophils, eosinophils, and macrophages [ 60 ].…”

Effects of Levofloxacin, Aztreonam, and Colistin on Enzyme Synthesis by P. aeruginosa Isolated from Cystic Fibrosis Patients

“…Additionally, the increased expression of some of these inflammatory molecules is dependent on nuclear factor κB activation [ 15 , 16 ]. Moreover, recently it has been reported that 15-LOX may interact with secretory phospholipase A2 (sPLA2), contributing to sterile inflammation in chronic conditions with differences from classical inflammation on the cytokine level [ 17 ].…”

Breakthrough of extracellular vesicles in pathogenesis, diagnosis and treatment of osteoarthritis

“…Ha et al proposed that oxidative stress-EVs are distinct from lipopolysaccharide (LPS)-induced EVs. They activate Toll-like receptor 4 (a type of DAMP) via synergy between 15-lipoxygenase and secreted PLA 2, resulting in aseptic inflammation [ 57 ], which offers a new opportunity to limit aseptic inflammation. Raffaele et al found that in the dorsal root ganglion (DRG), neuronal-immune crosstalk can be mediated by neuronal exosomes taken up by macrophages, which initiate a feedback loop of elevations in ROS and exosomes, propagating long-term pain [ 99 ].…”