Macrophage-Derived Extracellular Vesicles Induce Long-Lasting Immunity Against Hepatitis C Virus Which Is Blunted by Polyunsaturated Fatty Acids.
Macrophage-Derived Extracellular Vesicles Induce Long-Lasting Immunity Against Hepatitis C Virus Which Is Blunted by Polyunsaturated Fatty Acids.
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DOI：
10.3389/fimmu.2018.00723
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发表时间：
2018
影响因子：
7.3
通讯作者：
Lange CM
中科院分区：
文献类型：
--
作者：
Cai C;Koch B;Morikawa K;Suda G;Sakamoto N;Rueschenbaum S;Akhras S;Dietz J;Hildt E;Zeuzem S;Welsch C;Lange CM
细胞外小泡(EVS)是细胞间通讯的重要媒介。在这项研究中，我们旨在进一步研究巨噬细胞来源的EV在丙型肝炎病毒(HCV)免疫反应中的作用，以及多不饱和脂肪酸(PUFAs)调节这种天然免疫方式的可能性。为此，从干扰素刺激的巨噬细胞培养或急、慢性丙型肝炎患者的血清中分离出EV，并通过电子显微镜、流式细胞仪、RNA测序和Western印迹分析对EV进行表征。在共培养模型中评估EVS对丙型肝炎病毒复制的影响。功能分析评估多不饱和脂肪酸对EV介导的抗病毒免疫的影响。我们发现，巨噬细胞在I型和II型干扰素刺激后不久就会分泌各种细胞因子，这种细胞因子可以协调一种快速但短暂的抗病毒状态。紧随其后的是巨噬细胞衍生的EV的产生，这对丙型肝炎病毒复制产生了一种晚而持久的抑制作用。值得注意的是，巨噬细胞暴露于多不饱和脂肪酸，这是免疫反应的重要调节因素，抑制了EV介导的抗病毒免疫反应。最后，来自丙型肝炎患者的EV在干扰素治疗期间也显示出长期的抗病毒活性。高加索人和日本人EV的抗病毒效果不同，这可能是由于他们对多不饱和脂肪酸的营养摄取不同所致。综上所述，我们的数据表明，巨噬细胞来源的EV介导了对丙型肝炎病毒复制的长期抑制作用，这可能会缩短建立有效的适应性免疫反应之前的时间，并可以被多不饱和脂肪酸钝化。
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.