Human Platelets Utilize Cycloxygenase-1 to Generate Dioxolane A3, a Neutrophil-activating Eicosanoid.

Abstract

Eicosanoids are important mediators of fever, pain, and inflammation that modulate cell signaling during acute and chronic disease. We show by using lipidomics that thrombin-activated human platelets generate a new type of eicosanoid that both stimulates and primes human neutrophil integrin (Mac-1) expression, in response to formylmethionylleucylphenylalanine. Detailed characterization proposes a dioxolane structure, 8-hydroxy-9,11-dioxolane eicosatetraenoic acid (dioxolane A3, DXA3). The lipid is generated in nanogram 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 1 and 4, cytosolic phospholipase A2 (cPLA2), Src tyrosine kinases, p38 MAPK, phospholipase C, and intracellular calcium. From data generated by purified COX isoforms and chemical oxidation, we propose that DXA3 is generated by release of an intermediate 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.

• Authors: Christine Hinz, Maceler Aldrovandi, Charis Uhlson, Lawrence J Marnett, Hilary J Longhurst, Timothy D Warner, Saydul Alam, David A Slatter, Sarah N Lauder, Keith Allen-Redpath, Peter W Collins, Robert C Murphy, Christopher P Thomas, Valerie B O'Donnell
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 291 Issue 26 Pg. 13448-64 (Jun 24 2016) ISSN: 1083-351X [Electronic] United States
• PMID: 27129261 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Dioxolanes
• Macrophage-1 Antigen
• Membrane Proteins
• Cyclooxygenase 1
• PTGS1 protein, human
• Ptgs1 protein, mouse
• Aspirin
• formal glycol

Topics

• Animals
• Aspirin (pharmacology)
• Blood Platelets (enzymology, immunology)
• Cyclooxygenase 1 (immunology, metabolism)
• Dioxolanes (immunology, metabolism)
• Immunity, Innate (drug effects, physiology)
• MAP Kinase Signaling System (drug effects, physiology)
• Macrophage-1 Antigen (immunology, metabolism)
• Male
• Membrane Proteins (immunology, metabolism)
• Mice
• Neutrophil Activation (drug effects, physiology)
• Neutrophils (immunology, metabolism)
• Platelet Activation (drug effects, physiology)