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dc.contributor.authorPuhm, Florian
dc.contributor.authorAfonyushkin, Taras
dc.contributor.authorResch, Ulrike
dc.contributor.authorObermayer, Georg
dc.contributor.authorRohde, Manfred
dc.contributor.authorPenz, Thomas
dc.contributor.authorSchuster, Michael
dc.contributor.authorWagner, Gabriel
dc.contributor.authorRendeiro, Andre F
dc.contributor.authorMelki, Imene
dc.contributor.authorKaun, Christoph
dc.contributor.authorWojta, Johann
dc.contributor.authorBock, Christoph
dc.contributor.authorJilma, Bernd
dc.contributor.authorMackman, Nigel
dc.contributor.authorBoilard, Eric
dc.contributor.authorBinder, Christoph J
dc.identifier.citationCirc Res. 2019 Jun 21;125(1):43-52. doi: 10.1161/CIRCRESAHA.118.314601. Epub 2019 May 8.en_US
dc.description.abstractExtracellular vesicles, including microvesicles, are increasingly recognized as important mediators in cardiovascular disease. The cargo and surface proteins they carry are considered to define their biological activity, including their inflammatory properties. Monocyte to endothelial cell signaling is a prerequisite for the propagation of inflammatory responses. However, the contribution of microvesicles in this process is poorly understood. OBJECTIVE: To elucidate the mechanisms by which microvesicles derived from activated monocytic cells exert inflammatory effects on endothelial cells. METHODS AND RESULTS: LPS (lipopolysaccharide)-stimulated monocytic cells release free mitochondria and microvesicles with mitochondrial content as demonstrated by flow cytometry, quantitative polymerase chain reaction, Western Blot, and transmission electron microscopy. Using RNAseq analysis and quantitative reverse transcription-polymerase chain reaction, we demonstrated that both mitochondria directly isolated from and microvesicles released by LPS-activated monocytic cells, as well as circulating microvesicles isolated from volunteers receiving low-dose LPS-injections, induce type I IFN (interferon), and TNF (tumor necrosis factor) responses in endothelial cells. Depletion of free mitochondria significantly reduced the ability of these microvesicles to induce type I IFN and TNF-dependent genes. We identified mitochondria-associated TNFα and RNA from stressed mitochondria as major inducers of these responses. Finally, we demonstrated that the proinflammatory potential of microvesicles and directly isolated mitochondria were drastically reduced when they were derived from monocytic cells with nonrespiring mitochondria or monocytic cells cultured in the presence of pyruvate or the mitochondrial reactive oxygen species scavenger MitoTEMPO. CONCLUSIONS: Mitochondria and mitochondria embedded in microvesicles constitute a major subset of extracellular vesicles released by activated monocytes, and their proinflammatory activity on endothelial cells is determined by the activation status of their parental cells. Thus, mitochondria may represent critical intercellular mediators in cardiovascular disease and other inflammatory settings associated with type I IFN and TNF signaling.en_US
dc.publisherLippincott,Williams & Wilkinsen_US
dc.rightsAttribution-NonCommercial-ShareAlike 4.0 International*
dc.subjectendothelial cellsen_US
dc.subjectextracellular vesiclesen_US
dc.titleMitochondria Are a Subset of Extracellular Vesicles Released by Activated Monocytes and Induce Type I IFN and TNF Responses in Endothelial Cells.en_US
dc.contributor.departmentHZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.en_US
dc.identifier.journalCirculation researchen_US
dc.source.journaltitleCirculation research

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