Macrophage-Derived Extracellular Vesicles Induce Long-Lasting Immunity Against Hepatitis C Virus Which Is Blunted by Polyunsaturated Fatty Acids

Abstract

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.

Characterization of Cellular Sources and Circulating Levels of Extracellular Vesicles in a Dietary Murine Model of Nonalcoholic Steatohepatitis

“…Similarly, adipose tissue macrophage‐derived EVs can influence systemic insulin resistance in obesity . Macrophage‐derived EVs can influence anti‐hepatitis C immune responses and placental inflammatory responses . Adipose tissue expansion and inflammation are a component of obesity‐associated metabolic syndrome in our mouse dietary model and in humans with NASH .…”

Potential interventions for novel coronavirus in China: A systematic review

“…Long-chain polyunsaturated fatty acids (PUFAs) are important mediators of inflammation and adaptive immune responses. 31 Omega-3…”

“…They are precursors of resolvins/protectins and prostaglandins/leukotrienes, respectively. 31 Begin et al 32 had studied plasma lipids levels in patients with AIDS and had found that a selective and specific lack of the long-chain PUFAs of omega-3 series, which are found in high concentrations in fish oils. In addition, protectin D1, the omega-3 PUFA-derived lipid mediator, could markedly attenuate influenza virus replication via RNA export machinery.…”

Macrophage-derived extracellular vesicles: diverse mediators of pathology and therapeutics in multiple diseases

“…Interestingly, it seems that macrophages may have certain mechanisms to mediate the release pattern and synergistic effects of cytokines and EVs in response to infections. For example, macrophages orchestrate a fast but short-lasting antiviral state by secreting cytokines during HCV infection, while their EVs induce a late but long-lasting inhibition on HCV replication in hepatocytes with sub-genomic HCV replicons 124 . These studies suggest that Mφ-EVs may boost the anti-infective immune response by delivering viral materials or therapeutic molecules.…”