M2 Macrophages Play Critical Roles in Progression of Inflammatory Liver Disease in Hepatitis C Virus Transgenic Mice.
M2 Macrophages Play Critical Roles in Progression of Inflammatory Liver Disease in Hepatitis C Virus Transgenic Mice.
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M2巨噬细胞在肝炎病毒转基因小鼠的炎症性肝病进展中起关键作用。
DOI：
10.1128/jvi.02293-15
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发表时间：
2016-01-01
影响因子：
5.4
通讯作者：
Kohara M
中科院分区：
文献类型：
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作者：
Ohtsuki T;Kimura K;Tokunaga Y;Tsukiyama-Kohara K;Tateno C;Hayashi Y;Hishima T;Kohara M
肝组织中的巨噬细胞因其促炎症活性而被广泛定义为慢性病毒性肝炎中重要的炎症细胞。我们以前报道过白细胞介素-6（IL-6）和肿瘤坏死因子-α（TNF-α）在丙型肝炎病毒（HCV）转基因小鼠慢性肝炎的发生中起重要作用。Sekiguchi等人，PLoS One 7：e51656，2012，http：//dx·doi·org/10·1371/journal·pone·0051656）。此外，我们发现，表达HCV非结构蛋白（rVV-N25）的重组牛痘病毒可以通过抑制巨噬细胞活化来防止慢性肝炎的进展。在这里，我们专注于巨噬细胞在HCV转基因小鼠肝脏疾病进展中的作用，并研究rVV-N25治疗后巨噬细胞的特征。与年龄匹配的对照小鼠相比，HCV转基因小鼠肝脏中CD 11b + F4/80+ CD 11 c − CD 206+（M2）巨噬细胞的数量显著增加。肝脏中的这些M2巨噬细胞产生升高水平的IL-6和TNF-α。rVV-N25感染抑制肝组织中M2巨噬细胞的数量和活化。这些结果表明，M2样巨噬细胞产生的炎性细胞因子有助于诱导HCV转基因小鼠的慢性肝脏炎症。rVV-N_（25）的治疗作用可能是通过抑制肝巨噬细胞的数量和活化而实现的。重要性HCV引起持续感染，可导致慢性肝病、肝纤维化和肝细胞癌;寻找HCV治疗药物是正在进行的研究的重点。最近，已经开发了有效的抗HCV药物;然而，仍然需要开发疫苗来预防和治疗这种病毒的感染。我们在这里证明了M2巨噬细胞对于HCV引起的肝脏疾病的发病机制很重要，并且还表明M2巨噬细胞有助于rVV-N25治疗后观察到的治疗机制。
Macrophages in liver tissue are widely defined as important inflammatory cells in chronic viral hepatitis due to their proinflammatory activity. We reported previously that interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) play significant roles in causing chronic hepatitis in hepatitis C virus (HCV) transgenic mice (S. Sekiguchi et al., PLoS One 7:e51656, 2012, http://dx.doi.org/10.1371/journal.pone.0051656). In addition, we showed that recombinant vaccinia viruses expressing an HCV nonstructural protein (rVV-N25) could protect against the progression of chronic hepatitis by suppression of macrophage activation. Here, we focus on the role of macrophages in liver disease progression in HCV transgenic mice and examine characteristic features of macrophages following rVV-N25 treatment. The number of CD11b+ F4/80+ CD11c− CD206+ (M2) macrophages in the liver of HCV transgenic mice was notably increased compared to that of age-matched control mice. These M2 macrophages in the liver produced elevated levels of IL-6 and TNF-α. rVV-N25 infection suppressed the number and activation of M2 macrophages in liver tissue. These results suggested that inflammatory cytokines produced by M2-like macrophages contribute to the induction of chronic liver inflammation in HCV transgenic mice. Moreover, the therapeutic effect of rVV-N25 might be induced by the suppression of the number and activation of hepatic macrophages. IMPORTANCE HCV causes persistent infections that can lead to chronic liver diseases, liver fibrosis, and hepatocellular carcinoma; the search for an HCV curative is the focus of ongoing research. Recently, effective anti-HCV drugs have been developed; however, vaccine development still is required for the prevention and therapy of infection by this virus. We demonstrate here that M2 macrophages are important for the pathogenesis of HCV-caused liver diseases and additionally show that M2 macrophages contribute to the therapeutic mechanism observed following rVV-N25 treatment.