Mitochondria Are a Subset of Extracellular Vesicles Released by Activated Monocytes and Induce Type I IFN and TNF Responses in Endothelial Cells

Author:

Puhm Florian12,Afonyushkin Taras12,Resch Ulrike3,Obermayer Georg12,Rohde Manfred4,Penz Thomas2,Schuster Michael2,Wagner Gabriel1,Rendeiro Andre F.2,Melki Imene5,Kaun Christoph6,Wojta Johann678,Bock Christoph12,Jilma Bernd9,Mackman Nigel10,Boilard Eric5,Binder Christoph J.12

Affiliation:

1. From the Department of Laboratory Medicine (F.P., T.A., G.O., G.W., C.B., C.J.B.)

2. Research Center for Molecular Medicine (CeMM) of the Austrian Academy of Sciences, Vienna (F.P., T.A., G.O., T.P., M.S., A.F.R., C.B., C.J.B.)

3. Center of Physiology and Pharmacology (U.R.)

4. Central Facility for Microscopy, Helmholtz Centre for Infection Research, Braunschweig, Germany (M.R.)

5. Department of Infectious Diseases and Immunity, Faculty of Medicine, Centre de Recherche du Centre Hospitalier Universitaire de Québec, Université Laval, Quebec City, Canada (I.M., E.B.)

6. Department of Internal Medicine II (C.K., J.W.)

7. Core Facilities (J.W.)

8. Ludwig Boltzmann Cluster for Cardiovascular Research, Vienna, Austria (J.W.)

9. Department of Clinical Pharmacology (B.J.), Medical University of Vienna, Austria

10. Division of Hematology and Oncology, Department of Medicine, University of North Carolina at Chapel Hill (N.M.).

Abstract

Rationale: Extracellular 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.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine,Physiology

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3