10.3389/fimmu.2018.00723.s001 Chengcong Cai Chengcong Cai Benjamin Koch Benjamin Koch Kenichi Morikawa Kenichi Morikawa Goki Suda Goki Suda Naoya Sakamoto Naoya Sakamoto Sabrina Rueschenbaum Sabrina Rueschenbaum Sami Akhras Sami Akhras Julia Dietz Julia Dietz Eberhard Hildt Eberhard Hildt Stefan Zeuzem Stefan Zeuzem Christoph Welsch Christoph Welsch Christian M. Lange Christian M. Lange Data_Sheet_1.PDF Frontiers 2018 exosomes interferon innate immunity omega-3 fatty acids arachidonic acid 2018-04-12 09:53:01 Dataset https://frontiersin.figshare.com/articles/dataset/Data_Sheet_1_PDF/6133286 <p>Extracellular vesicles (EVs) are increasingly recognized as important mediators of intercellular communication. In this study, we aimed to further characterize the role of macrophage-derived EVs in immune responses against hepatitis C virus (HCV) and the potential of polyunsaturated fatty acids (PUFAs) to modulate this modality of innate immunity. To this end, EVs were isolated from interferon-stimulated macrophage cultures or from serum of patients with acute or chronic hepatitis C. EVs were characterized by electron microscopy, flow cytometry, RNA-sequencing, and Western blot analysis. The effect of EVs on replication of HCV was assessed in coculture models. Functional analyses were performed to assess the impact of PUFAs on EV-mediated antiviral immunity. We found that macrophages secreted various cytokines shortly after stimulation with type I and II IFN, which orchestrated a fast but short-lasting antiviral state. This rapid innate immune answer was followed by the production of macrophage-derived EVs, which induced a late, but long-lasting inhibitory effect on HCV replication. Of note, exposure of macrophages to PUFAs, which are important regulators of immune responses, dampened EV-mediated antiviral immune responses. Finally, EVs from patients with hepatitis C exhibited long-lasting antiviral activities during IFN therapy as well. The antiviral effect of EVs from Caucasian and Japanese patients differed, which may be explained by different nutritional uptake of PUFAs. In conclusion, our data indicate that macrophage-derived EVs mediate long-lasting inhibitory effects on HCV replication, which may bridge the time until efficient adaptive immune responses are established, and which can be blunted by PUFAs.</p>