- Hinz C, Aldrovandi M, Uhlson C, Marnett LJ, Longhurst HJ, Warner TD, Alam S, Slatter DA, Lauder SN, Allen-Redpath K, Collins PW, Murphy RC, Thomas CP, O'Donnell VB. Human platelets utilize cycloxygenase-1 to generate dioxolane A3, a neutrophil activating eicosanoid. The Journal of Biological Chemistry. 2016 Apr 22. PMID: 27129261 [PubMed].
Eicosanoids are important mediators of fever, pain and inflammation that modulate cell signaling during acute and chronic disease. We show using lipidomics, that thrombin-activated human platelets generate a new type of eicosanoid which both stimulates and primes human neutrophil integrin (Mac-1) expression, in response to fMLP . Detailed characterization supports a dioxolane (DX) structure, 8-hydroxy-9,11-dioxolane eicosatriaenoic acid (dioxolane A3, DXA3). The lipid is generated in ng amounts by platelets from endogenous arachidonate during physiological activation, with inhibition by aspirin in vitro or in vivo, implicating cyclooxygenase-1 (COX). Pharmacological and genetic studies on human/murine platelets revealed that DXA3 formation requires protease-activated receptors (PAR) 1 and 4, cytosolic phospholipase A2 (cPLA2), src tyrosine kinases, p38 MAP kinase, phospholipase C and intracellular calcium. From data generated by purified COX isoforms and chemical oxidation, we propose that DXA3 is generated release of a dioxolane from the active site followed by oxygenation at C8. In summary, a new neutrophil- activating platelet-derived lipid generated by COX-1 is presented, that can activate or prime human neutrophils, suggesting a role in innate immunity and acute inflammation.