@article{MTMT:33055762, title = {The roles of extracellular vesicles in the immune system}, url = {https://m2.mtmt.hu/api/publication/33055762}, author = {Buzás, Edit Irén}, doi = {10.1038/s41577-022-00763-8}, journal-iso = {NAT REV IMMUNOL}, journal = {NATURE REVIEWS IMMUNOLOGY}, volume = {23}, unique-id = {33055762}, issn = {1474-1733}, abstract = {The twenty-first century has witnessed major developments in the field of extracellular vesicle (EV) research, including significant steps towards defining standard criteria for the separation and detection of EVs. The recent recognition that EVs have the potential to function as biomarkers or as therapeutic tools has attracted even greater attention to their study. With this progress in mind, an updated comprehensive overview of the roles of EVs in the immune system is timely. This Review summarizes the roles of EVs in basic processes of innate and adaptive immunity, including inflammation, antigen presentation, and the development and activation of B cells and T cells. It also highlights key progress related to deciphering the roles of EVs in antimicrobial defence and in allergic, autoimmune and antitumour immune responses. It ends with a focus on the relevance of EVs to immunotherapy and vaccination, drawing attention to ongoing or recently completed clinical trials that aim to harness the therapeutic potential of EVs. Extracellular vesicles (EVs) are increasingly recognized as having ubiquitous roles in the immune system. This Review focuses on the progress made in the field in the past 5 years, including the roles of EVs in innate and adaptive immunity and their potential use in diagnosis and therapy.}, keywords = {ANTIGEN; T-CELLS; B-CELLS; FOLLICULAR DENDRITIC CELLS; MEMBRANE-VESICLES; MICROVESICLES; EMERGING ROLE; Cell-derived exosomes; DOWN-MODULATE}, year = {2023}, eissn = {1474-1741}, pages = {236-250}, orcid-numbers = {Buzás, Edit Irén/0000-0002-3744-206X} } @article{MTMT:32553054, title = {A brief history of nearly EV-erything - The rise and rise of extracellular vesicles}, url = {https://m2.mtmt.hu/api/publication/32553054}, author = {Couch, Yvonne and Buzás, Edit Irén and Vizio, Dolores Di and Gho, Yong Song and Harrison, Paul and Hill, Andrew F. and Lotvall, Jan and Raposo, Graca and Stahl, Philip D. and Thery, Clotilde and Witwer, Kenneth W. and Carter, David R. F.}, doi = {10.1002/jev2.12144}, journal-iso = {J EXTRACELLULAR VESICL}, journal = {JOURNAL OF EXTRACELLULAR VESICLES}, volume = {10}, unique-id = {32553054}, abstract = {Extracellular vesicles (EVs) are small cargo-bearing vesicles released by cells into the extracellular space. The field of EVs has grown exponentially over the past two decades; this growth follows the realisation that EVs are not simply a waste disposal system as had originally been suggested by some, but also a complex cell-to-cell communication mechanism. Indeed, EVs have been shown to transfer functional cargo between cells and can influence several biological processes. These small biological particles are also deregulated in disease. As we approach the 75th anniversary of the first experiments in which EVs were unknowingly isolated, it seems right to take stock and look back on how the field started, and has since exploded into its current state. Here we review the early experiments, summarise key findings that have propelled the field, describe the growth of an organised EV community, discuss the current state of the field, and identify key challenges that need to be addressed.}, year = {2021}, eissn = {2001-3078}, orcid-numbers = {Buzás, Edit Irén/0000-0002-3744-206X} } @article{MTMT:32289889, title = {Extracellular vesicle release and uptake by the liver under normo- and hyperlipidemia}, url = {https://m2.mtmt.hu/api/publication/32289889}, author = {Németh, Krisztina and Varga, Zoltán and Lenzinger, Dorina and Visnovitz, Tamás and Koncz, Anna and Hegedűs, Nikolett and Kittel, Ágnes and Máthé, Domokos and Szigeti, Krisztián and Lőrincz, Péter and O'Neill, Clodagh and Dwyer, Róisín and Liu, Zhonglin and Buzás, Edit Irén and Tamási, Viola}, doi = {10.1007/s00018-021-03969-6}, journal-iso = {CELL MOL LIFE SCI}, journal = {CELLULAR AND MOLECULAR LIFE SCIENCES}, volume = {78}, unique-id = {32289889}, issn = {1420-682X}, abstract = {Liver plays a central role in elimination of circulating extracellular vesicles (EVs), and it also significantly contributes to EV release. However, the involvement of the different liver cell populations remains unknown. Here, we investigated EV uptake and release both in normolipemia and hyperlipidemia. C57BL/6 mice were kept on high fat diet for 20-30 weeks before circulating EV profiles were determined. In addition, control mice were intravenously injected with 99mTc-HYNIC-Duramycin labeled EVs, and an hour later, biodistribution was analyzed by SPECT/CT. In vitro, isolated liver cell types were tested for EV release and uptake with/without prior fatty acid treatment. We detected an elevated circulating EV number after the high fat diet. To clarify the differential involvement of liver cell types, we carried out in vitro experiments. We found an increased release of EVs by primary hepatocytes at concentrations of fatty acids comparable to what is characteristic for hyperlipidemia. When investigating EV biodistribution with 99mTc-labeled EVs, we detected EV accumulation primarily in the liver upon intravenous injection of mice with medium (326.3 ± 19.8 nm) and small EVs (130.5 ± 5.8 nm). In vitro, we found that medium and small EVs were preferentially taken up by Kupffer cells, and liver sinusoidal endothelial cells, respectively. Finally, we demonstrated that in hyperlipidemia, there was a decreased EV uptake both by Kupffer cells and liver sinusoidal endothelial cells. Our data suggest that hyperlipidema increases the release and reduces the uptake of EVs by liver cells. We also provide evidence for a size-dependent differential EV uptake by the different cell types of the liver. The EV radiolabeling protocol using 99mTc-Duramycin may provide a fast and simple labeling approach for SPECT/CT imaging of EVs biodistribution.}, keywords = {Kupffer cell; hepatocyte; extracellular vesicle; Liver sinusoidal endothelial cells; Extracellular particles}, year = {2021}, eissn = {1420-9071}, pages = {7589-7604}, orcid-numbers = {Németh, Krisztina/0000-0002-3825-2137; Varga, Zoltán/0000-0002-5741-2669; Visnovitz, Tamás/0000-0002-7962-5083; Koncz, Anna/0000-0003-2511-2394; Hegedűs, Nikolett/0000-0003-1122-1872; Lőrincz, Péter/0000-0001-7374-667X; Buzás, Edit Irén/0000-0002-3744-206X; Tamási, Viola/0000-0001-7419-5603} } @article{MTMT:3107860, title = {MicroRNA Cargo of Extracellular Vesicles from Alcohol-exposed Monocytes Signals Naive Monocytes to Differentiate into M2 Macrophages}, url = {https://m2.mtmt.hu/api/publication/3107860}, author = {Saha, B and Momen-Heravi, F and Kodys, K and Szabó, Gyöngyi}, doi = {10.1074/jbc.M115.694133}, journal-iso = {J BIOL CHEM}, journal = {JOURNAL OF BIOLOGICAL CHEMISTRY}, volume = {291}, unique-id = {3107860}, issn = {0021-9258}, abstract = {Membrane-coated extracellular vesicles (EVs) released by cells can serve as vehicles for delivery of biological materials and signals. Recently, we demonstrated that alcohol-treated hepatocytes cross-talk with immune cells via exosomes containing microRNA (miRNAs). Here, we hypothesized that alcohol-exposed monocytes can communicate with naive monocytes via EVs. We observed increased numbers of EVs, mostly exosomes, secreted by primary human monocytes and THP-1 monocytic cells in the presence of alcohol in a concentration- and time-dependent manner. EVs derived from alcohol-treated monocytes stimulated naive monocytes to polarize into M2 macrophages as indicated by increased surface expression of CD68 (macrophage marker), M2 markers (CD206 (mannose receptor) and CD163 (scavenger receptor)), secretion of IL-10, and TGF and increased phagocytic activity. miRNA profiling of the EVs derived from alcohol-treated THP-1 monocytes revealed high expression of the M2-polarizing miRNA, miR-27a. Treatment of naive monocytes with control EVs overexpressing miR-27a reproduced the effect of EVs from alcohol-treated monocytes on naive monocytes and induced M2 polarization, suggesting that the effect of alcohol EVs was mediated by miR-27a. We found that miR-27a modulated the process of phagocytosis by targeting CD206 expression on monocytes. Importantly, analysis of circulating EVs from plasma of alcoholic hepatitis patients revealed increased numbers of EVs that contained high levels of miR-27a as compared with healthy controls. Our results demonstrate the following: first, alcohol increases EV production in monocytes; second, alcohol-exposed monocytes communicate with naive monocytes via EVs; and third, miR-27a cargo in monocyte-derived EVs can program naive monocytes to polarize into M2 macrophages.}, keywords = {PHAGOCYTOSIS; ACTIVATION; INTERFERON-ALPHA; DENDRITIC CELLS; innate immunity; LIVER-DISEASE; liver injury; cell signaling; MICROVESICLES; Exosomes; Extracellular vesicles; CIRCULATING MICRORNAS; THP-1 CELLS; exosome (vesicle); Alcoholic Hepatitis}, year = {2016}, eissn = {1083-351X}, pages = {149-159} } @article{MTMT:2976220, title = {Biodistribution and function of extracellular miRNA-155 in mice}, url = {https://m2.mtmt.hu/api/publication/2976220}, author = {Bala, S and Csák, Tímea and Momen-Heravi, F and Lippai, Dóra and Kodys, K and Catalano, D and Satishchandran, A and Ambros, V and Szabó, Gyöngyi}, doi = {10.1038/srep10721}, journal-iso = {SCI REP}, journal = {SCIENTIFIC REPORTS}, volume = {5}, unique-id = {2976220}, abstract = {Circulating miRNAs can be found in extracellular vesicles (EV) and could be involved in intercellular communication. Here, we report the biodistribution of EV associated miR-155 using miR-155 KO mouse model. Administration of exosomes loaded with synthetic miR-155 mimic into miR-155 KO mice resulted in a rapid accumulation and clearance of miR-155 in the plasma with subsequent distribution in the liver, adipose tissue, lung, muscle and kidney (highest to lowest, respectively). miR-155 expression was detected in isolated hepatocytes and liver mononuclear cells of recipient KO mice suggesting its cellular uptake. In vitro, exosome-mediated restoration of miR-155 in Kupffer cells from miR-155 deficient mice augmented their LPS-induced MCP1 mRNA increase. The systemic delivery of wild type plasma to miR-155 KO mice also resulted in a rapid accumulation of miR-155 in the circulation and distribution to the liver and adipose tissue. In summary, our results demonstrate tissue biodistribution and biologic function of EV-associated miR-155.}, year = {2015}, eissn = {2045-2322} } @article{MTMT:3106717, title = {Exosomes derived from alcohol-treated hepatocytes horizontally transfer liver specific miRNA-122 and sensitize monocytes to LPS}, url = {https://m2.mtmt.hu/api/publication/3106717}, author = {Momen-Heravi, F and Bala, S and Kodys, K and Szabó, Gyöngyi}, doi = {10.1038/srep09991}, journal-iso = {SCI REP}, journal = {SCIENTIFIC REPORTS}, volume = {5}, unique-id = {3106717}, abstract = {Hepatocyte damage and inflammation in monocytes/macrophages are central to the pathogenesis of alcoholic hepatitis (AH). MicroRNAs (miRNAs) regulate all of these processes. MiRNA-122 is abundantly expressed in hepatocytes while monocytes/macrophages have low levels. The role of exosomes in AH and possible cross talk between hepatocyte-derived exosomes and immune cells is not explored yet. Here, we show that the number of exosomes significantly increases in the sera of healthy individuals after alcohol binge drinking and in mice after binge or chronic alcohol consumption. Exosomes isolated from sera after alcohol consumption or from in vitro ethanol-treated hepatocytes contained miRNA-122. Exosomes derived from ethanol-treated Huh7.5 cells were taken up by the recipients THP1 monocytes and horizontally transferred a mature form of liver-specific miRNA-122. In vivo, liver mononuclear cells and Kupffer cells from alcohol-fed mice had increased miRNA-122 levels. In monocytes, miRNA-122 transferred via exosomes inhibited the HO-1 pathway and sensitized to LPS stimulation and increased levels of pro-inflammatory cytokines. Finally, inflammatory effects of exosomes from ethanol-treated hepatocytes were prevented by using RNA interference via exosome-mediated delivery of a miRNA-122 inhibitor. These results demonstrate that first, exosomes mediate communication between hepatocytes and monocytes/macrophages and second, hepatocyte-derived miRNA-122 can reprogram monocytes inducing sensitization to LPS.}, year = {2015}, eissn = {2045-2322} } @article{MTMT:3106727, title = {Exosomes from Hepatitis C Infected Patients Transmit HCV Infection and Contain Replication Competent Viral RNA in Complex with Ago2-miR122-HSP90}, url = {https://m2.mtmt.hu/api/publication/3106727}, author = {Bukong, TN and Momen-Heravi, F and Kodys, K and Bala, S and Szabó, Gyöngyi}, doi = {10.1371/journal.ppat.1004424}, journal-iso = {PLOS PATHOG}, journal = {PLOS PATHOGENS}, volume = {10}, unique-id = {3106727}, issn = {1553-7366}, abstract = {Antibodies targeting receptor-mediated entry of HCV into hepatocytes confer limited therapeutic benefits. Evidence suggests that exosomes can transfer genetic materials between cells; however, their role in HCV infection remains obscure. Here, we show that exosomes isolated from sera of chronic HCV infected patients or supernatants of J6/JFH1-HCV-infected Huh7.5 cells contained HCV RNA. These exosomes could mediate viral receptor-independent transmission of HCV to hepatocytes. Negative sense HCV RNA, indicative of replication competent viral RNA, was present in exosomes of all HCV infected treatment non-responders and some treatment-naive individuals. Remarkably, HCV RNA was associated with Ago2, HSP90 and miR-122 in exosomes isolated from HCV-infected individuals or HCV-infected Huh7.5 cell supernatants. Exosome-loading with a miR-122 inhibitor, or inhibition of HSP90, vacuolar H+-ATPases, and proton pumps, significantly suppressed exosome-mediated HCV transmission to naive cells. Our findings provide mechanistic evidence for HCV transmission by blood-derived exosomes and highlight potential therapeutic strategies.}, year = {2014}, eissn = {1553-7374} } @article{MTMT:2059128, title = {Increased microRNA-155 expression in the serum and peripheral monocytes in chronic HCV infection.}, url = {https://m2.mtmt.hu/api/publication/2059128}, author = {Bala, S and Tilahun, Y and Taha, O and Alao, H and Kodys, K and Catalano, D and Szabó, Gyöngyi}, doi = {10.1186/1479-5876-10-151}, journal-iso = {J TRANSL MED}, journal = {JOURNAL OF TRANSLATIONAL MEDICINE}, volume = {10}, unique-id = {2059128}, issn = {1479-5876}, abstract = {ABSTRACT: BACKGROUND: Hepatitis C Virus (HCV), a single stranded RNA virus, affects millions of people worldwide and leads to chronic infection characterized by chronic inflammation in the liver and in peripheral immune cells. Chronic liver inflammation leads to progressive liver damage. MicroRNAs (miRNA) regulate inflammation (miR-155, -146a and -125b) as well as hepatocyte function (miR-122). METHODS: Here we hypothesized that microRNAs are dysregulated in chronic HCV infection. We examined miRNAs in the circulation and in peripheral monocytes of patients with chronic HCV infection to evaluate if specific miRNA expression correlated with HCV infection. RESULTS: We found that monocytes from chronic HCV infected treatment-naive (cHCV) but not treatment responder patients showed increased expression of miR-155, a positive regulator of TNFalpha, and had increased TNFalpha production compared to monocytes of normal controls. After LPS stimulation, miR-155 levels were higher in monocytes from cHCV patients compared to controls. MiR-125b, which has negative regulatory effects on inflammation, was decreased in cHCV monocytes compared to controls. Stimulation of normal monocytes with TLR4 and TLR8 ligands or HCV core, NS3 and NS5 recombinant proteins induced a robust increase in both miR-155 expression and TNFalpha production identifying potential mechanisms for in vivo induction of miR-155. Furthermore, we found increased serum miR-155 levels in HCV patients compared to controls. Serum miR-125b and miR-146a levels were also increased in HCV patients. Serum levels of miR-122 were elevated in cHCV patients and correlated with increased ALT and AST levels and serum miR-155 levels. CONCLUSION: In conclusion, our novel data demonstrate that miR-155, a positive regulator of inflammation, is upregulated both in monocytes and in the serum of patients with chronic HCV infection. Our study suggests that HCV core, NS3, and NS5 proteins or TLR4 and TLR8 ligands can mediate increased miR-155 and TNFalpha production in chronic HCV infection. The positive correlation between serum miR-155 and miR-122 increase in cHCV may be an indicator of inflammation-induced hepatocyte damage.}, year = {2012}, eissn = {1479-5876} }