Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 27, Pages E3564-E3573Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1507905112
Keywords
platelets; microparticles; neutrophils; 12-lipoxygenase; phospholipase A(2)
Categories
Funding
- Canadian Institutes of Health Research
- Arthritis Society
- Canadian Arthritis Network
- Fonds de Recherche du Quebec en Sante
- Fonds de Recherche des maladies Rhumatismales de l'Universite Laval
- Canadian Blood Services
- CNRS
- French National Research Agency (Investments for the Future, Labex SIGNALIFE) [NR-11-LABX-0028-01]
- National Institutes of Health [R37 HL36235]
- Canadian Institutes of Health Research New Investigator Award
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Platelets are anucleated blood elements highly potent at generating extracellular vesicles (EVs) called microparticles (MPs). Whereas EVs are accepted as an important means of intercellular communication, the mechanisms underlying platelet MP internalization in recipient cells are poorly understood. Our lipidomic analyses identified 12(S)-hydroxyeicosatetranoic acid [12(S)-HETE] as the predominant eicosanoid generated by MPs. Mechanistically, 12(S)-HETE is produced through the concerted activity of secreted phospholipase A(2) IIA (sPLA(2)-IIA), present in inflammatory fluids, and platelet-type 12-lipoxygenase (12-LO), expressed by platelet MPs. Platelet MPs convey an elaborate set of transcription factors and nucleic acids, and contain mitochondria. We observed that MPs and their cargo are internalized by activated neutrophils in the endomembrane system via 12(S)-HETE. Platelet MPs are found inside neutrophils isolated from the joints of arthritic patients, and are found in neutrophils only in the presence of sPLA(2)-IIA and 12-LO in an in vivo model of autoimmune inflammatory arthritis. Using a combination of genetically modified mice, we show that the coordinated action of sPLA(2)-IIA and 12-LO promotes inflammatory arthritis. These findings identify 12(S)-HETE as a trigger of platelet MP internalization by neutrophils, a mechanism highly relevant to inflammatory processes. Because sPLA(2)-IIA is induced during inflammation, and 12-LO expression is restricted mainly to platelets, these observations demonstrate that platelet MPs promote their internalization in recipient cells through highly regulated mechanisms.
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