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

Boudreau, Luc H; Duchez, Anne-Claire; Cloutier, Nathalie; Soulet, Denis LU ; Martin, Nicolas; Bollinger, James; Paré, Alexandre; Rousseau, Matthieu; Naika, Gajendra S and Lévesque, Tania, et al. (2014) In Blood 124(14). p.83-2173
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... (More)

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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@misc{b5bf8c14-e159-4b74-941c-1ae891ac57d9,
  abstract     = {<p>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.</p>},
  author       = {Boudreau, Luc H and Duchez, Anne-Claire and Cloutier, Nathalie and Soulet, Denis and Martin, Nicolas and Bollinger, James and Paré, Alexandre and Rousseau, Matthieu and Naika, Gajendra S and Lévesque, Tania and Laflamme, Cynthia and Marcoux, Geneviève and Lambeau, Gérard and Farndale, Richard W and Pouliot, Marc and Hamzeh-Cognasse, Hind and Cognasse, Fabrice and Garraud, Olivier and Nigrovic, Peter A and Guderley, Helga and Lacroix, Steve and Thibault, Louis and Semple, John W and Gelb, Michael H and Boilard, Eric},
  issn         = {1528-0020},
  keyword      = {Animals,Blood Platelets,DNA, Mitochondrial,Endothelium, Vascular,Flow Cytometry,Group II Phospholipases A2,Humans,Inflammation,Male,Mice,Mice, Inbred C57BL,Mitochondria,Platelet Activation,Rickettsia prowazekii,Journal Article,Research Support, N.I.H., Extramural,Research Support, Non-U.S. Gov't},
  language     = {eng},
  month        = {10},
  number       = {14},
  pages        = {83--2173},
  publisher    = {ARRAY(0x93933d0)},
  series       = {Blood},
  title        = {Platelets release mitochondria serving as substrate for bactericidal group IIA-secreted phospholipase A2 to promote inflammation},
  url          = {http://dx.doi.org/10.1182/blood-2014-05-573543},
  volume       = {124},
  year         = {2014},
}