Journal
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
Volume 34, Issue 3, Pages 571-580Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.113.302919
Keywords
activated platelets; foam cells; monocytes; oxidized low-density lipoprotein; P-selectin; platelet factor 4; platelet inhibitors
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Funding
- Austrian Science Fund [FWF P-24978-B13]
- Swedish Research Council-Medicine [K2011-569-20937-01-3]
- Swedish Heart-Lung Foundation [2010/0614]
- CERIC (Center of Excellence for Research on Inflammation and Cardiovascular disease, Swedish Research Council) [70870302]
- Cardiovascular Program and Stockholm County Council
- Austrian Science Fund (FWF) [P 24978] Funding Source: researchfish
- Austrian Science Fund (FWF) [P24978] Funding Source: Austrian Science Fund (FWF)
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Objective A growing body of evidence indicates that platelets contribute to the onset and progression of atherosclerosis by modulating immune responses. We aimed to elucidate the effects of oxidized low-density lipoprotein (OxLDL) on platelet-monocyte interactions and the consequences of these interactions on platelet phagocytosis, chemokine release, monocyte extravasation, and foam cell formation. Approach and Results Confocal microscopy and flow cytometric analysis revealed that in vitro and in vivo stimulation with OxLDL resulted in rapid formation of platelet-monocyte aggregates, with a preference for CD16+ monocyte subsets. This platelet-monocyte interaction facilitated OxLDL uptake by monocytes, in a process that involved platelet CD36-OxLDL interaction, release of chemokines, such as CXC motif ligand 4, direct platelet-monocyte interaction, and phagocytosis of platelets. Inhibition of cyclooxygenase with acetylsalicylic acid and antagonists of ADP receptors, P2Y1 and P2Y12, partly abrogated OxLDL-induced platelet-monocyte aggregates and platelet-mediated lipid uptake in monocytes. Platelets also enhanced OxLDL-induced monocyte transmigration across an endothelial monolayer via direct interaction with monocytes in a transwell assay. Importantly, in LDLR-/- mice, platelet depletion resulted in a significant decrease of peritoneal macrophage recruitment and foam cell formation in a thioglycollate-elicited peritonitis model. In platelet-depleted wild-type mice, transfusion of ex vivo OxLDL-stimulated platelets induced monocyte extravasation to a higher extent when compared with resting platelets. Conclusions Our results on OxLDL-mediated platelet-monocyte aggregate formation, which promoted phenotypic changes in monocytes, monocyte extravasation and enhanced foam cell formation in vitro and in vivo, provide a novel mechanism for how platelets potentiate key steps of atherosclerotic plaque development and plaque destabilization.
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