Synergy between 15-lipoxygenase and secreted PLA <sub>2</sub> promotes inflammation by formation of TLR4 agonists from extracellular vesicles
Van Thai Ha, Duško Lainšček, Bernd Gesslbauer, Eva Jarc Jovičić, Tuulia Hyötyläinen, Nejc Ilc, Katja Lakota, Matija Tomšič, Fons A. J. van de Loo, Valery N. Bochkov, Toni Petan, Roman Jerala, Mateja Manček‐Keber
Abstract
Significance Oxidative stress, which accompanies sterile inflammation, induces release of extracellular vesicles (stressEVs), which activate Toll-like receptor 4 (TLR4), resulting in a pattern of gene expression distinct from response triggered by bacterial lipopolysaccharide. The synergy between 15-lipoxygenase and secreted phospholipase A 2 , both of which are induced by stress, is necessary for the formation of oxidized lysophospholipids, TLR4 endogenous agonists. Moreover, TLR4 was necessary for sPLA 2 promoted K/BxN serum-induced arthritis. As the formation of TLR4 agonists is enzyme driven, it provides an opportunity to inhibit these enzymes to limit sterile inflammation.