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

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.