Platelets release mitochondria serving as substrate for bactericidal group IIA-secreted phospholipase A2 to promote inflammation

Blood. 2014 Oct 2;124(14):2173-83. doi: 10.1182/blood-2014-05-573543.

Luc H Boudreau ¹, Anne-Claire Duchez ¹, Nathalie Cloutier ¹, Denis Soulet ², Nicolas Martin ³, James Bollinger ⁴, Alexandre Paré ², Matthieu Rousseau ¹, Gajendra S Naika ⁴, Tania Lévesque ¹, Cynthia Laflamme ¹, Geneviève Marcoux ¹, Gérard Lambeau ⁵, Richard W Farndale ⁶, Marc Pouliot ¹, Hind Hamzeh-Cognasse ⁷, Fabrice Cognasse ⁷, Olivier Garraud ⁷, Peter A Nigrovic ⁸, Helga Guderley ³, Steve Lacroix ², Louis Thibault ⁹, John W Semple ¹⁰, Michael H Gelb ⁴, Eric Boilard ¹

Affiliations

1 Centre de Recherche du Centre Hospitalier Universitaire de Québec, Faculté de Médecine de l'Université Laval, Département de Microbiologie et Immunologie, Quebec, QC, Canada;
2 Centre de Recherche du Centre Hospitalier Universitaire de Québec, Faculté de Médecine de l'Université Laval, Département de Psychiatrie et Neurosciences, Quebec, QC, Canada;
3 Département de Biologie, Université Laval, Quebec, QC, Canada;
4 Department of Chemistry, University of Washington, Seattle, WA;
5 Institut de Pharmacologie Moléculaire et Cellulaire, Unité Mixte de Recherche 7275, Centre National de la Recherche Scientifique-Université Nice Sophia Antipolis, Valbonne, France;
6 Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom;
7 Etablissement Français du Sang Auvergne-Loire and Université de Lyon, Saint-Etienne, France;
8 Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, and Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA;
9 Research and Development, Héma-Québec, Quebec, QC, Canada; and.
10 The Keenan Research Center in the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, ON, Canada.

PMID: 25082876 DOI: 10.1182/blood-2014-05-573543

Abstract

Mitochondrial DNA (mtDNA) is a highly potent inflammatory trigger and is reportedly found outside the cells in blood in various pathologies. Platelets are abundant in blood where they promote hemostasis. Although lacking a nucleus, platelets contain functional mitochondria. On activation, platelets produce extracellular vesicles known as microparticles. We hypothesized that activated platelets could also release their mitochondria. We show that activated platelets release respiratory-competent mitochondria, both within membrane-encapsulated microparticles and as free organelles. Extracellular mitochondria are found in platelet concentrates used for transfusion and are present at higher levels in those that induced acute reactions (febrile nonhemolytic reactions, skin manifestations, and cardiovascular events) in transfused patients. We establish that the mitochondrion is an endogenous substrate of secreted Phospholipase A2 IIA (sPLA2-IIA), a Phospholipase otherwise specific for bacteria, likely reflecting the ancestral proteobacteria origin of mitochondria. The hydrolysis of the mitochondrial membrane by sPLA2-IIA yields inflammatory mediators (ie, lysophospholipids, fatty acids, and mtDNA) that promote leukocyte activation. Two-photon microscopy in live transfused Animals revealed that extracellular mitochondria interact with neutrophils in vivo, triggering neutrophil adhesion to the endothelial wall. Our findings identify extracellular mitochondria, produced by platelets, at the midpoint of a potent mechanism leading to inflammatory responses.

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