Body Fluid Exosomes Promote Secretion of Inflammatory Cytokines in Monocytic Cells via Toll-like Receptor Signaling

Bretz, Niko P.; Ridinger, Johannes; Rupp, Anne-Kathleen; Rimbach, Katharina; Keller, Sascha; Rupp, Christian; Marmé, Frederik; Umansky, Ludmila; Umansky, Viktor; Eigenbrod, Tatjana; Sammar, Marei; Altevogt, Peter

doi:10.1074/jbc.m113.512806

Cited by 208 publications

(189 citation statements)

References 45 publications

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“…However, mild activation is known to be protective (Mathur et al 2011. Other studies have suggested a link between body fluid exosomes and TLR-dependent signaling pathways, possibly mediating immunosuppressive and anti-inflammatory pathways (Bretz et al 2013, Zhang et al 2014.…”

Section: Evs As a Potential Therapy For Cardiometabolic Diseasementioning

confidence: 99%

Microvesicles and exosomes: new players in metabolic and cardiovascular disease

Lawson¹,

Vicencio²,

Yellon³

et al. 2016

Journal of Endocrinology

282

241

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The past decade has witnessed an exponential increase in the number of publications referring to extracellular vesicles (EVs). For many years considered to be extracellular debris, EVs are now seen as novel mediators of endocrine signalling via cell-to-cell communication.With the capability of transferring proteins and nucleic acids from one cell to another, they have become an attractive focus of research for different pathological settings and are now regarded as both mediators and biomarkers of disease including cardio-metabolic disease. They also offer therapeutic potential as signalling agents capable of targeting tissues or cells with specific peptides or miRNAs. In this review, we focus on the role that microvesicles (MVs) and exosomes, the two most studied classes of EV, have in diabetes, cardiovascular disease, endothelial dysfunction, coagulopathies, and polycystic ovary syndrome. We also provide an overview of current developments in MV/exosome isolation techniques from plasma and other fluids, comparing different available commercial and non-commercial methods. We describe different techniques for their optical/biochemical characterization and quantitation. We also review the signalling pathways that exosomes and MVs activate in target cells and provide some insight into their use as biomarkers or potential therapeutic agents. In summary, we give an updated focus on the role that these exciting novel nanoparticles offer for the endocrine community.

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Section: Evs As a Potential Therapy For Cardiometabolic Diseasementioning

confidence: 99%

Microvesicles and exosomes: new players in metabolic and cardiovascular disease

Lawson¹,

Vicencio²,

Yellon³

et al. 2016

Journal of Endocrinology

282

241

View full text Add to dashboard Cite

show abstract

“…Clayton and colleagues reported that TEX selectively impaired human lymphocyte responses to IL-2 (48). TEX-delivered signals trigger the activation of NF-κB and STAT3 (51) and alter cytokine profiles in T cells, reprogramming them toward the Th2 phenotype (51). TEX signal to monocytes, inducing secretion of the proinflammatory cytokines IL-6, TNF-α, IL-1β, and granulocyte-CSF (G-CSF) (52).…”

Section: Functional Attributes Of Texmentioning

confidence: 99%

Exosomes and tumor-mediated immune suppression

Whiteside¹

2016

Journal of Clinical Investigation

444

376

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Tumor-derived exosomes (TEX) are harbingers of tumor-induced immune suppression: they carry immunosuppressive molecules and factors known to interfere with immune cell functions. By delivering suppressive cargos consisting of proteins similar to those in parent tumor cells to immune cells, TEX directly or indirectly influence the development, maturation, and antitumor activities of immune cells. TEX also deliver genomic DNA, mRNA, and microRNAs to immune cells, thereby reprogramming functions of responder cells to promote tumor progression. TEX carrying tumor-associated antigens can interfere with antitumor immunotherapies. TEX also have the potential to serve as noninvasive biomarkers of tumor progression. In the tumor microenvironment, TEX may be involved in operating numerous signaling pathways responsible for the downregulation of antitumor immunity.

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“…The delayed activation of STAT-3 in vascular smooth muscle cells and in response to tumor-derived exosomes in THP-1 cells has been reported (48,57). In this study, exosomal blockade in hypertrophied cardiomyocytes had no effect on STAT-3 phosphorylation in myocyte-conditioned fibroblasts at earlier time points; however, it dampened STAT-3 activity at later phases.…”

Section: Fig 11mentioning

confidence: 37%

“…Besides occurring in a secreted form, IL-6 may also reside in cell-derived exosomes, as suggested earlier (48). Myocyte-derived exosomes have not yet been characterized during AngII-mediated hypertrophy.…”

Section: Fig 11mentioning

confidence: 86%

Myocyte-Derived Hsp90 Modulates Collagen Upregulation via Biphasic Activation of STAT-3 in Fibroblasts during Cardiac Hypertrophy

Datta

Bansal

Rana

et al. 2017

Molecular and Cellular Biology

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Signal transducer and activator of transcription 3 (STAT-3)-mediated signaling in relation to upregulated collagen expression in fibroblasts during cardiac hypertrophy is well defined. Our recent findings have identified heat shock protein 90 (Hsp90) to be a critical modulator of fibrotic signaling in cardiac fibroblasts in this disease milieu. The present study was therefore intended to analyze the role of Hsp90 in the STAT-3-mediated collagen upregulation process. Our data revealed a significant difference between in vivo and in vitro results, pointing to a possible involvement of myocyte-fibroblast cross talk in this process. Cardiomyocyte-targeted knockdown of Hsp90 in rats (Rattus norvegicus) in which the renal artery was ligated showed downregulated collagen synthesis. Furthermore, the results obtained with cardiac fibroblasts conditioned with Hsp90-inhibited hypertrophied myocyte supernatant pointed toward cardiomyocytes' role in the regulation of collagen expression in fibroblasts during hypertrophy. Our study also revealed a novel signaling mechanism where myocyte-derived Hsp90 orchestrates not only p65-mediated interleukin-6 (IL-6) synthesis but also its release in exosomal vesicles. Such myocyte-derived exosomes and myocyte-secreted IL-6 are responsible in unison for the biphasic activation of STAT-3 signaling in cardiac fibroblasts that culminates in excess collagen synthesis, leading to severely compromised cardiac function during cardiac hypertrophy.KEYWORDS cardiac hypertrophy, collagen, Hsp90, myocyte-fibroblast cross talk, STAT-3 M yocardial fibrosis is a hallmark of cardiac hypertrophy and a proposed substrate for heart failure (1, 2). The extracellular space is frequently the site for such abnormal accumulation of fibrillar collagen, accounting for myocardial stiffness and ventricular dysfunction during cardiac hypertrophy (3). The cardiac fibroblast is the principal cell type in the myocardium and synthesizes and secretes collagen in response to pressure-overload hypertrophy (4). A close relationship between angiotensin II (AngII) and profibrotic cytokines has been suggested, and several molecular signaling networks have been implicated in the progression of cardiac fibrosis (5, 6). A few reports have also shown that the role of myocytes in myocardial collagen production is mediated by myocyte-derived paracrine factors (7,8). However, the precise mechanisms involving the role of different signaling intermediates in the regulation of collagen gene expression during cardiac hypertrophy have remained unsolved.In an earlier report, we described the mechanism of interleukin-6 (IL-6)-mediated activation of the signal transducer and activator of transcription 3 (STAT-3) and consequent collagen synthesis in the hypertrophied rat heart (9). STAT-3 activation has also

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Body Fluid Exosomes Promote Secretion of Inflammatory Cytokines in Monocytic Cells via Toll-like Receptor Signaling

Cited by 208 publications

References 45 publications

Microvesicles and exosomes: new players in metabolic and cardiovascular disease

Microvesicles and exosomes: new players in metabolic and cardiovascular disease

Exosomes and tumor-mediated immune suppression

Myocyte-Derived Hsp90 Modulates Collagen Upregulation via Biphasic Activation of STAT-3 in Fibroblasts during Cardiac Hypertrophy

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