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Phospholipase A₂ regulates eicosanoid class switching during inflammasome activation
- Norris, Paul C., Gosselin, David, Reichart, Donna, Glass, Christopher K., Dennis, Edward A.
- Proceedings of the National Academy of Sciences of the United States of America 2014 v.111 no.35 pp. 12746-12751
- Toll-like receptor 4, adenosine triphosphate, arachidonic acid, aspirin, biosynthesis, endotoxins, esterification, humans, hydrolysis, inflammation, interleukin-1, macrophages, models, neutrophils, phospholipase A2, phospholipids, secretion
- Initiation and resolution of inflammation are considered to be tightly connected processes. Lipoxins (LX) are proresolution lipid mediators that inhibit phlogistic neutrophil recruitment and promote wound-healing macrophage recruitment in humans via potent and specific signaling through the LXA ₄ receptor (ALX). One model of lipoxin biosynthesis involves sequential metabolism of arachidonic acid by two cell types expressing a combined transcellular metabolon. It is currently unclear how lipoxins are efficiently formed from precursors or if they are directly generated after receptor-mediated inflammatory commitment. Here, we provide evidence for a pathway by which lipoxins are generated in macrophages as a consequence of sequential activation of toll-like receptor 4 (TLR4), a receptor for endotoxin, and P2X ₇, a purinergic receptor for extracellular ATP. Initial activation of TLR4 results in accumulation of the cyclooxygenase-2–derived lipoxin precursor 15-hydroxyeicosatetraenoic acid (15-HETE) in esterified form within membrane phospholipids, which can be enhanced by aspirin (ASA) treatment. Subsequent activation of P2X ₇ results in efficient hydrolysis of 15-HETE from membrane phospholipids by group IVA cytosolic phospholipase A ₂, and its conversion to bioactive lipoxins by 5-lipoxygenase. Our results demonstrate how a single immune cell can store a proresolving lipid precursor and then release it for bioactive maturation and secretion, conceptually similar to the production and inflammasome-dependent maturation of the proinflammatory IL-1 family cytokines. These findings provide evidence for receptor-specific and combinatorial control of pro- and anti-inflammatory eicosanoid biosynthesis, and potential avenues to modulate inflammatory indices without inhibiting downstream eicosanoid pathways.