KLRG1 +天然杀伤细胞在慢性乙型肝炎中发挥新的抗纤维化功能

StephenW

J Hepatol. 2019 Mar 21. pii: S0168-8278(19)30182-5. doi: 10.1016/j.jhep.2019.03.012. [Epub ahead of print]
KLRG1+ natural killer cells exert a novel anti-fibrotic function in chronic hepatitis B.
Wijaya RS1, Read SA2, Schibeci S3, Eslam M3, Azardaryany MK3, El-Khobar K3, van der Poorten D4, Lin R4, Yuen L5, Lam V5, George J6, Douglas MW7, Ahlenstiel G8.
Author information

1
    Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW 2145, Australia; Faculty of Medicine, Pelita Harapan University, Tangerang, Indonesia.
2
    Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW 2145, Australia; Blacktown Clinical School, Western Sydney University, Blacktown, NSW 2148.
3
    Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW 2145, Australia.
4
    Westmead Hospital, University of Sydney, NSW, Australia.
5
    Westmead Hospital, University of Sydney, NSW, Australia; Discipline of Surgery, University of Sydney, Australia.
6
    Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW 2145, Australia; Westmead Hospital, University of Sydney, NSW, Australia.
7
    Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW 2145, Australia; Westmead Hospital, University of Sydney, NSW, Australia; Centre for Infectious Diseases and Microbiology, Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney at Westmead Hospital, Westmead NSW 2145, Australia.
8
    Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW 2145, Australia; Blacktown Clinical School, Western Sydney University, Blacktown, NSW 2148; Blacktown Hospital, Blacktown, NSW 2148, Australia. Electronic address: [email protected].

Abstract
BACKGROUND & AIMS:

Natural killer (NK) cells are known to exert strong antiviral activity. Killer cell lectin-like receptor subfamily G member 1 (KLRG1) is expressed by terminally differentiated NK cells and KLRG1-expressing lymphocytes are known to expand following chronic viral infections. The role of KLRG1 in pathogenesis of chronic hepatitis B (CHB) remains unknown.
METHODS:

Phenotype and function of KLRG1+ NK cells from blood and liver of patients with CHB and healthy individuals was assessed using flow cytometry and in vitro stimulation.
RESULTS:

CHB patients had a higher frequency of KLRG1+ NK cells compared to healthy controls (blood 13.4 vs. 2.3%, p<0.0001 and liver 23.4 vs 2.6%, p<0.01). KLRG1+ NK cells were less responsive to K562 and cytokine stimulation, but demonstrated enhanced cytotoxicity (9 vs. 4.8%, p<0.05) and IFN-γ release (8 vs. 1.5%, p<0.05) via antibody dependent cellular cytotoxicity compared to their KLRG1- counterparts. KLRG1+ NK cells possessed a mature phenotype, demonstrated stronger cytolytic activity and IFN-γ secretion than KLRG1- NK cells against hepatic stellate cells (HSCs). Moreover, KLRG1+ NK cells more effectively induced primary HSCs apoptosis in a TRAIL-dependent manner. Increased KLRG1+ NK cell frequency in liver and blood was associated with lower fibrosis stage (F0/F1) in patients with CHB. Finally, KLRG1+ NK cells had higher expression of CD44 and increased degranulation and IFN-γ production following stimulation with osteopontin, the CD44 ligand, suggesting that HSCs derived osteopontin may cause KLRG1+ NK cells activation.
CONCLUSIONS:

KLRG1+ NK cells likely play an anti-fibrotic role during the natural course of CHB infection. Harnessing this anti-fibrotic function provide a novel therapeutic approach to treat liver fibrosis in CHB.
LAY SUMMARY:

Individuals that are chronically infected with hepatitis B virus (HBV) possess an increased number of immune cells, called natural killer (NK) cells expressing the surface marker KLRG1 in the blood and liver. Here, we demonstrate that these specific NK cells are able to kill activated stellate cells in the liver. Because activated stellate cells contribute to liver scarring, i.e. fibrosis, and subsequent liver dysfunction in individuals with chronic HBV infection, KLRG1+ NK cells are a novel immune cell type that can limit liver scarring.

Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
KEYWORDS:

Hepatitis B virus; Liver fibrosis; Natural killer cells

PMID:
    30905683
DOI:
    10.1016/j.jhep.2019.03.012

StephenW

J Hepatol。 2019年3月21日.pii：S0168-8278（19）30182-5。 doi：10.1016 / j.jhep.2019.03.012。 [印刷前的电子版]
KLRG1 +天然杀伤细胞在慢性乙型肝炎中发挥新的抗纤维化功能。
Wijaya RS1，Read SA2，Schibeci S3，Eslam M3，Azardaryany MK3，El-Khobar K3，van der Poorten D4，Lin R4，Yuen L5，Lam V5，George J6，Douglas MW7，Ahlenstiel G8。
作者信息

1
    Storr肝脏中心，悉尼大学Westmead医学研究所，Westmead，NSW 2145，澳大利亚;印度尼西亚坦格朗佩利塔哈拉潘大学医学院。
2
    Storr肝脏中心，悉尼大学Westmead医学研究所，Westmead，NSW 2145，澳大利亚;新南威尔士州2148，布莱克敦，西悉尼大学布莱克敦临床学校。
3
    Storr肝脏中心，悉尼大学Westmead医学研究所，Westmead，NSW 2145，澳大利亚。
4
    澳大利亚新南威尔士州悉尼大学Westmead医院。
五
    澳大利亚新南威尔士州悉尼大学Westmead医院;澳大利亚悉尼大学外科学科。
6
    Storr肝脏中心，悉尼大学Westmead医学研究所，Westmead，NSW 2145，澳大利亚;澳大利亚新南威尔士州悉尼大学Westmead医院。
7
    Storr肝脏中心，悉尼大学Westmead医学研究所，Westmead，NSW 2145，澳大利亚;澳大利亚新南威尔士州悉尼大学Westmead医院;澳大利亚新南威尔士州韦斯特米德2145 Westmead医院悉尼大学传染病与生物安全研究所传染病与微生物学中心。
8
    Storr肝脏中心，悉尼大学Westmead医学研究所，Westmead，NSW 2145，澳大利亚;新南威尔士州2148，布莱克敦，西悉尼大学布莱克敦临床学校;布莱克敦医院，布莱克敦，新南威尔士州2148，澳大利亚。电子地址：[email protected]。

抽象
背景与目的：

已知自然杀伤（NK）细胞发挥强烈的抗病毒活性。杀伤细胞凝集素样受体亚家族G成员1（KLRG1）由终末分化的NK细胞表达，并且已知表达KLRG1的淋巴细胞在慢性病毒感染后扩增。 KLRG1在慢性乙型肝炎（CHB）发病机制中的作用尚不清楚。
方法：

使用流式细胞术和体外刺激评估CHB患者和健康个体的血液和肝脏的KLRG1 + NK细胞的表型和功能。
结果：

与健康对照相比，CHB患者具有更高频率的KLRG1 + NK细胞（血液13.4对2.3％，p <0.0001，肝脏23.4对2.6％，p <0.01）。 KLRG1 + NK细胞对K562和细胞因子刺激的反应较弱，但通过抗体依赖性细胞毒作用表现出增强的细胞毒性（9％对4.8％，p <0.05）和IFN-γ释放（8对1.5％，p <0.05）。他们的KLRG1-同行。 KLRG1 + NK细胞具有成熟表型，表现出比KLRG1-NK细胞对肝星状细胞（HSC）更强的细胞溶解活性和IFN-γ分泌。此外，KLRG1 + NK细胞以TRAIL依赖性方式更有效地诱导原代HSC凋亡。肝脏和血液中KLRG1 + NK细胞频率的增加与CHB患者的纤维化阶段（F0 / F1）较低有关。最后，CD44配体骨桥蛋白刺激后，KLRG1 + NK细胞CD44表达增加，脱颗粒和IFN-γ产生增加，提示HSC来源骨桥蛋白可能导致KLRG1 + NK细胞活化。
结论：

KLRG1 + NK细胞可能在CHB感染的自然过程中发挥抗纤维化作用。利用这种抗纤维化功能提供了一种治疗CHB肝纤维化的新方法。
LAY总结：

长期感染乙型肝炎病毒（HBV）的个体具有增加数量的免疫细胞，称为自然杀伤（NK）细胞，其在血液和肝脏中表达表面标志物KLRG1。在这里，我们证明这些特定的NK细胞能够杀死肝脏中活化的星状细胞。因为活化的星状细胞导致肝脏瘢痕形成，即纤维化，以及随后的慢性HBV感染个体的肝功能障碍，KLRG1 + NK细胞是一种可以限制肝脏瘢痕形成的新型免疫细胞类型。

版权所有©2019欧洲肝脏研究协会。由Elsevier B.V.发布。保留所有权利。
关键词：

乙型肝炎病毒;肝纤维化;自然杀手细胞

结论：
    30905683
DOI：