DioxolaneA3-phosphatidylethanolamines are generated by human platelets and stimulate neutrophil integrin expression

Abstract

Activated platelets generate an eicosanoid proposed to be 8-hydroxy-9,10-dioxolane A3 (DXA3). Herein, we demonstrate that significant amounts of DXA3 are rapidly attached to phosphatidylethanolamine (PE) forming four esterified eicosanoids, 16:0p, 18:0p, 18:1p and 18:0a/DXA3-PEs that can activate neutrophil integrin expression. These lipids comprise the majority of DXA3 generated by platelets, are formed in ng amounts (24.3±6.1 ng/2×108) and remain membrane bound. Pharmacological studies revealed DXA3-PE formation involves cyclooxygenase-1 (COX), protease-activated receptors (PAR) 1 and 4, cytosolic phospholipase A2 (cPLA2), phospholipase C and intracellular calcium. They are generated primarily via esterification of newly formed DXA3, but can also be formed in vitro via co-oxidation of PE during COX-1 co-oxidation of arachidonate. All four DXA3-PEs were detected in human clots. Purified platelet DXA3-PE activated neutrophil Mac-1 expression, independently of its hydrolysis to the free eicosanoid. This study demonstrates the structures and cellular synthetic pathway for a family of leukocyte-activating platelet phospholipids generated on acute activation, adding to the growing evidence that enzymatic PE oxidation is a physiological event in innate immune cells.

PEBP1 Wardens Ferroptosis by Enabling Lipoxygenase Generation of Lipid Death Signals

“…While historically these free oxygenated PUFA were associated with many signaling functions, lately it has become obvious that a more diversified group of PLox represent a much richer signaling language albeit with a poorly understood role. It has been shown that AA-PEox are required for normal functions of many types of leukocytes (Aldrovandi et al, 2017; Morgan et al, 2009), are meaningful signals in phagocytosis of apoptotic cells (Uderhardt et al, 2012) and represent crucial death signals in ferroptosis (Kagan et al, 2017). …”

Enzymatically oxidized phospholipids assume center stage as essential regulators of innate immunity and cell death

“…In addition to 12-LOX, platelets can also generate eoxPL through COX-1, specifically prostaglandin E 2 (PGE 2 )-PE and PGD 2 -PE (41,42). However, despite the quantitatively high abundance of thromboxane-B 2 , attachment of this eicosanoid to PLs has not been detected.…”

Platelet lipidome: Dismantling the “Trojan horse” in the bloodstream

“…DXA3 is rapidly esterified to 16:0‐, 18:1‐, 18:0‐PE‐plasmalogen, and 18:0‐acyl‐PE by lysophospholipid acyltransferases (Figure A); so mostly remains platelet associated, while free DXA3 adds to serum levels during clotting. Platelet‐derived/associated DXA3 enhances neutrophil Mac‐1 expression (CD11b/CD18), which might exaggerate neutrophil‐platelet or endothelial associations, transendothelial migration, and phagocytosis. Discovery of more platelet‐derived lipids and their pathophysiological relevance will uncover novel thromboinflammatory mediators and therapeutic targets.…”