title: Platelet microparticles are internalized in neutrophils via the concerted activity of 12-lipoxygenase and secreted phospholipase A2-IIA.
abstract: 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 A2 IIA (sPLA2-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 sPLA2-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 sPLA2-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 sPLA2-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.
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire de Québec, Département de Microbiologie et Immunologie, Faculté de Médecine, Université Laval, Québec, QC, G1V 4G2 Canada;
authors.forename: Anne-Claire
authors.initials: AC
authors.lastname: Duchez
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire de Québec, Département de Microbiologie et Immunologie, Faculté de Médecine, Université Laval, Québec, QC, G1V 4G2 Canada;
authors.forename: Luc H
authors.initials: LH
authors.lastname: Boudreau
authors.forename: Gajendra S
authors.initials: GS
authors.lastname: Naika
authors.affiliation: Department of Chemistry, University of Washington, Seattle, WA 98195;
authors.forename: James
authors.initials: J
authors.lastname: Bollinger
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire de Québec, Département d'Obstétrique, Gynécologie et Reproduction, Faculté de Médecine, Université Laval, Québec, QC, G1V 4G2 Canada;
authors.forename: Clémence
authors.initials: C
authors.lastname: Belleannée
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire de Québec, Département de Microbiologie et Immunologie, Faculté de Médecine, Université Laval, Québec, QC, G1V 4G2 Canada;
authors.forename: Nathalie
authors.initials: N
authors.lastname: Cloutier
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire de Québec, Département de Microbiologie et Immunologie, Faculté de Médecine, Université Laval, Québec, QC, G1V 4G2 Canada;
authors.forename: Benoit
authors.initials: B
authors.lastname: Laffont
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire de Québec, Département d'Obstétrique, Gynécologie et Reproduction, Faculté de Médecine, Université Laval, Québec, QC, G1V 4G2 Canada;
authors.forename: Raifish E
authors.initials: RE
authors.lastname: Mendoza-Villarroel
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire de Québec, Département de Microbiologie et Immunologie, Faculté de Médecine, Université Laval, Québec, QC, G1V 4G2 Canada;
authors.forename: Tania
authors.initials: T
authors.lastname: Lévesque
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire de Québec, Département de Microbiologie et Immunologie, Faculté de Médecine, Université Laval, Québec, QC, G1V 4G2 Canada;
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Rollet-Labelle
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire de Québec, Département de Microbiologie et Immunologie, Faculté de Médecine, Université Laval, Québec, QC, G1V 4G2 Canada;
authors.forename: Matthieu
authors.initials: M
authors.lastname: Rousseau
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire de Québec, Département de Microbiologie et Immunologie, Faculté de Médecine, Université Laval, Québec, QC, G1V 4G2 Canada;
authors.forename: Isabelle
authors.initials: I
authors.lastname: Allaeys
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire de Québec, Département d'Obstétrique, Gynécologie et Reproduction, Faculté de Médecine, Université Laval, Québec, QC, G1V 4G2 Canada;
authors.forename: Jacques J
authors.initials: JJ
authors.lastname: Tremblay
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire de Québec, Département de Microbiologie et Immunologie, Faculté de Médecine, Université Laval, Québec, QC, G1V 4G2 Canada;
authors.forename: Patrice E
authors.initials: PE
authors.lastname: Poubelle
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, UMR 7275, Centre National de la Recherche Scientifique, Université de Nice Sophia Antipolis, 06250 Valbonne, France;
authors.forename: Gérard
authors.initials: G
authors.lastname: Lambeau
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire de Québec, Département de Microbiologie et Immunologie, Faculté de Médecine, Université Laval, Québec, QC, G1V 4G2 Canada;
authors.forename: Marc
authors.initials: M
authors.lastname: Pouliot
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire de Québec, Département de Microbiologie et Immunologie, Faculté de Médecine, Université Laval, Québec, QC, G1V 4G2 Canada;
authors.forename: Patrick
authors.initials: P
authors.lastname: Provost
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire de Québec, Département de Psychiatrie et Neurosciences, Faculté de Médecine, Université Laval, Québec, QC, G1V 4G2 Canada.
authors.forename: Denis
authors.initials: D
authors.lastname: Soulet
authors.affiliation: Department of Chemistry, University of Washington, Seattle, WA 98195;
authors.forename: Michael H
authors.initials: MH
authors.lastname: Gelb
authors.affiliation: Centre de Recherche du Centre Hospitalier Universitaire de Québec, Département de Microbiologie et Immunologie, Faculté de Médecine, Université Laval, Québec, QC, G1V 4G2 Canada; eric.boilard@crchudequebec.ulaval.ca.
authors.forename: Eric
authors.initials: E
authors.lastname: Boilard
mesh_terms: D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / Q000378:metabolism; D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D001169:Arthritis, Experimental / Q000235:genetics / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000378:metabolism; D001792:Blood Platelets / Q000201:enzymology / Q000378:metabolism*; D002460:Cell Line; D055252:Cell-Derived Microparticles / Q000201:enzymology / Q000378:metabolism* / Q000648:ultrastructure; D002478:Cells, Cultured; D004705:Endocytosis; D054501:Group II Phospholipases A2 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D008928:Mitochondria / Q000378:metabolism / Q000648:ultrastructure; D009504:Neutrophils / Q000378:metabolism* / Q000648:ultrastructure; D012313:RNA / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013582:Synovial Fluid / Q000378:metabolism
chemical_list: D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D012313:RNA; D001092:Arachidonate 12-Lipoxygenase; D054501:Group II Phospholipases A2
keywords: 12-lipoxygenase; microparticles; neutrophils; phospholipase A2; platelets