title: Platelets mediate oxidized low-density lipoprotein-induced monocyte extravasation and foam cell formation.
abstract: 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.
  
  
  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.
authors.affiliation: From the Institute of Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria (S.B., W.C.S., J.B.K., I.V., G.S., A.A.); and Department of Medicine, Solna, Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden (K.-C.Y., C.S.-N., A.A.).
authors.forename: Sigrun
authors.initials: S
authors.lastname: Badrnya
authors.forename: Waltraud C
authors.initials: WC
authors.lastname: Schrottmaier
authors.forename: Julia B
authors.initials: JB
authors.lastname: Kral
authors.forename: Koon-Chu
authors.initials: KC
authors.lastname: Yaiw
authors.forename: Ivo
authors.initials: I
authors.lastname: Volf
authors.forename: Gernot
authors.initials: G
authors.lastname: Schabbauer
authors.forename: Cecilia
authors.initials: C
authors.lastname: Söderberg-Nauclér
authors.forename: Alice
authors.initials: A
authors.lastname: Assinger
mesh_terms: D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D050197:Atherosclerosis / Q000503:physiopathology; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D039481:CD11b Antigen / Q000502:physiology; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D002633:Chemotaxis / Q000187:drug effects*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D005487:Foam Cells / Q000166:cytology / Q000187:drug effects*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008077:Lipoproteins, LDL / Q000494:pharmacology* / Q000633:toxicity; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology / Q000187:drug effects*; D019007:P-Selectin / Q000097:blood; D010538:Peritonitis / Q000139:chemically induced / Q000473:pathology; D010587:Phagocytosis / Q000187:drug effects; D010973:Platelet Adhesiveness / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D010978:Platelet Factor 4 / Q000502:physiology; D017713:Platelet Transfusion; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D057705:Transendothelial and Transepithelial Migration / Q000187:drug effects
chemical_list: D039481:CD11b Antigen; D018925:Chemokines; D052246:Cyclooxygenase 2 Inhibitors; C509295:ITGAM protein, human; D008077:Lipoproteins, LDL; D008562:Membrane Glycoproteins; D019007:P-Selectin; C084882:P-selectin ligand protein; D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D011973:Receptors, LDL; C099252:oxidized low density lipoprotein; D010978:Platelet Factor 4; D001241:Aspirin
keywords: P-selectin; activated platelets; foam cells; monocytes; oxidized low-density lipoprotein; platelet factor 4; platelet inhibitors