Activated hepatic stellate cells impair NK cell anti-fibrosis capacity through a TGF-β-dependent emperipolesis in HBV cirrhotic patients.
Activated hepatic stellate cells impair NK cell anti-fibrosis capacity through a TGF-β-dependent emperipolesis in HBV cirrhotic patients.
复制标题
HBV 肝硬化患者中激活的肝星状细胞通过 TGF-β 依赖性伸入作用损害 NK 细胞抗纤维化能力
DOI：
10.1038/srep44544
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发表时间：
2017-03-14
影响因子：
4.6
通讯作者：
Zhang Z
中科院分区：
文献类型：
--
作者：
Shi J;Zhao J;Zhang X;Cheng Y;Hu J;Li Y;Zhao X;Shang Q;Sun Y;Tu B;Shi L;Gao B;Wang FS;Zhang Z
自然杀伤细胞(NK细胞)可通过杀伤肝星状细胞(HSC)和产生干扰素-γ来诱导小鼠肝纤维化的缓解，但其抗纤维化免疫特性及其调节机制尚不清楚，尤其是在乙肝病毒感染的肝硬变(LC)患者的肝脏中。我们分析了43例乙肝-LC患者外周血和肝脏NK细胞亚群的频率、表型和抗纤维化功能。我们发现，与慢性乙型病毒性肝炎患者相比，LC患者肝脏NK细胞亚群的频率、活化状态和抗纤维化活性均降低，这主要是由肝内肿瘤生长因子-β升高所介导的，因为阻断转化生长因子-β在体外显著逆转了NK细胞的抗纤维化功能。在体内，肝NK细胞在轻度纤维化区的α-平滑肌肌动蛋白(α-SMA+)区附近富集区，而在重度纤维化区，它们要么直接附着于α-SMA+区，要么与其分离。LC患者外周血中的NK细胞可进入肝星状细胞形成胞间结构，并发生凋亡；抗转化生长因子-β治疗可改善这种病变。这一发现提示了一种新的机制，即活化的HSC通过转化生长因子-β依赖的血栓在LC患者中损害NK细胞的抗纤维化能力，通过增强NK细胞的活性来提供抗纤维化的理性。
Natural killer (NK) cells can induce liver fibrosis remission by killing hepatic stellate cells (HSCs) and producing interferon (IFN)-γ in a mouse model; however, their anti-fibrotic immune-characteristics and regulatory mechanisms by HSCs remain to be determined, especially in livers from HBV-infected liver cirrhosis (LC) patients. We analyzed frequency, phenotype and anti-fibrotic function of hepatic and peripheral NK subsets in 43 HBV-LC patients. We found that hepatic NK subsets from LC patients displayed a decreased frequency, activation status and anti-fibrotic activity compared with those from chronic hepatitis B patients, which were mainly mediated by increased intrahepatic tumour-growth factor (TGF)-β because blockade of TGF-β significantly reversed NK anti-fibrotic function in vitro. In vivo, hepatic NK cells were enriched in proximity to the α-smooth muscle actin (α-SMA+) area within mild fibrosis regions; while in severe fibrotic areas, they were either directly attached to or separated from the α-SMA+ region. NK cells from LC patients could enter HSCs to form emperipolesis (a cell-in-cell structure) and become apoptotic; anti-TGF-β treatment ameliorated this emperipolesis. This finding suggested a novel mechanism by which activated HSCs impair NK cells’ anti-fibrosis capacity through a TGF-β-dependent emperipolesis in LC patients, providing an anti-fibrotic rational by enhancing NK cell activity.