Functional role of CCL5/RANTES for HCC progression during chronic liver disease
Functional role of CCL5/RANTES for HCC progression during chronic liver disease
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DOI：
10.1016/j.jhep.2016.12.011
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发表时间：
2017-04-01
影响因子：
25.7
通讯作者：
Trautwein, Christian
中科院分区：
文献类型：
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作者：
Mohs, Antje;Kuttkat, Nadine;Trautwein, Christian
背景与目的：在肝脏炎症过程中，引发肝纤维化和癌变的免疫细胞起着关键作用。在本研究中，我们研究了CCL5在人和导致肝细胞癌(HCC)的慢性肝脏炎症小鼠模型中的作用。方法：研究CCL5及其受体在明确的慢性肝病(CLD)患者和两种基于炎症的小鼠肝细胞癌模型中的表达。在不同细胞群的Nemo Delta HEPA/CCL5(-/-)动物和骨髓移植(BMT)后，分析了CCL5在炎症、纤维化、肿瘤发生和发展中的作用。作为治疗干预，注射Evasin-4 24小时或8周。结果：在CLD患者中，CCL5及其受体CCR5过表达-在mdr2(-/-)和Nemo Delta HEPA模型中证实了这一观察结果。NEMODHepa小鼠CCL5缺失减少了肝细胞的凋亡、代偿性增殖和肝纤维化形成，这是由于免疫细胞浸润减少所致。尤其是CD45(+)/Ly6G(+)粒细胞、CD45(+)/CD11b(+)/Gr1.1(+)/F4/80(+)前炎症单核细胞、CD4(+)和CD8(+)T细胞减少。一岁的Nemo Delta HEPA/CCL5(/)小鼠肿瘤较小，恶性肿瘤较少，以增殖能力降低和血管生成较少为特征。我们发现造血细胞是CCL5的主要来源，而CCL5缺乏并不会使Nemo Delta HEPA肝细胞对肿瘤坏死因子α诱导的凋亡敏感。最后，在为期8周的治疗干预中，Evasin-4改善了肝病的进展。结论：我们确定了CCL5在人类和小鼠疾病进展中的重要作用，特别是在肝细胞癌的发展过程中。因此，一种在体内抑制CCL5的新方法对慢性肝病患者来说似乎是令人鼓舞的。总结：我们目前的研究确定了具有趋化吸引力的细胞因子CCL5在人类和小鼠肝脏疾病进展，特别是肝细胞癌发生中的重要作用。最后，CCL5的抑制似乎对人类慢性肝病的治疗是令人鼓舞的。(C)2016年欧洲肝脏研究协会。爱思唯尔出版公司版权所有。
Background & Aims: During liver inflammation, triggering fibrogenesis and carcinogenesis immune cells play a pivotal role. In the present study we investigated the role of CCL5 in human and in murine models of chronic liver inflammation leading to hepatocellular carcinoma (HCC) development.Methods: CCL5 expression and its receptors were studied in well-defined patients with chronic liver disease (CLD) and in two murine inflammation based HCC models. The role of CCL5 in inflammation, fibrosis, tumor initiation and progression was analyzed in different cell populations of NEMO Delta hepa/CCL5(-/-) animals and after bone marrow transplantation (BMT). For therapeutic intervention Evasin-4 was injected for 24 h or 8 weeks.Results: In CLD patients, CCL5 and its receptor CCR5 are overexpressed - an observation confirmed in the Mdr2(-/-) and NEMO Delta hepa model. CCL5 deletion in NEMODhepa mice diminished hepatocyte apoptosis, compensatory proliferation and fibrogenesis due to reduced immune cell infiltration. Especially, CD45(+)/ Ly6G(+) granulocytes, CD45(+)/CD11b(+)/Gr1.1(+)/F4/80(+) proinflammatory monocytes, CD4(+) and CD8(+) T cells were decreased. One year old NEMO Delta hepa/CCL5 (/) mice displayed smaller and less malignant tumors, characterized by reduced proliferative capacity and less pronounced angiogenesis. We identified hematopoietic cells as the main source of CCL5, while CCL5 deficiency did not sensitise NEMO Delta hepa hepatocytes towards TNF alpha induced apoptosis. Finally, therapeutic intervention with Evasin-4 over a period of 8 weeks ameliorated liver disease progression.Conclusion: We identified an important role of CCL5 in human and functionally in mice with disease progression, especially HCC development. A novel approach to inhibit CCL5 in vivo thus appears encouraging for patients with CLD.Lay summary: Our present study identifies the essential role of the chemoattractive cytokine CCL5 for liver disease progression and especially hepatocellular carcinoma development in men and mice. Finally, the inhibition of CCL5 appears to be encouraging for therapy of human chronic liver disease. (C) 2016 European Association for the Study of the Liver. Published by Elsevier B. V. All rights reserved.