肝内CD206 +巨噬细胞在晚期病毒相关肝脏疾病中有助于炎症

StephenW

Intrahepatic CD206+ macrophages contribute to inflammation in advanced viral-related liver disease
Alfonso Tan-Garcia†
, Lu-En Wai†
, Dahai Zheng
, Erica Ceccarello
, Juandy Jo
, Nasirah Banu
, Atefeh Khakpoor
, Adeline Chia
, Christine Y.L. Tham
, Anthony T. Tan
, Michelle Hong
, Choong Tat Keng
, Laura Rivino
, Kai Chah Tan
, Kang Hoe Lee
, Seng Gee Lim
, Evan W. Newell
, Norman Pavelka
, Jinmiao Chen
, Florent Ginhoux
, Qingfeng Chen‡
, Antonio Bertoletti‡
, Charles-Antoine Dutertre'Correspondence information about the author Charles-Antoine Dutertre‡,Email the author Charles-Antoine Dutertre
†These first authors contributed equally to this work.
‡Senior authors on this work.
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DOI: http://dx.doi.org/10.1016/j.jhep.2017.04.023 |

Highlights

    •Liver CD14+HLA-DRhiCD206+ cells accumulate in chronic viral-related liver disease.
    •CD14+HLA-DRhiCD206+ cells are pro-inflammatory and resistant to LPS tolerisation.
    •Gut microbiota influence accumulation of pro-inflammatory CD14+HLA-DRhiCD206+ cells.

Background & Aims

Liver inflammation is key in the progression of chronic viral hepatitis to cirrhosis and hepatocellular carcinoma. The magnitude of viral replication and the specific anti-viral immune responses should govern the degree of inflammation, but a direct correlation is not consistently found in chronic viral hepatitis patients. We aim to better define the mechanisms that contribute to chronic liver inflammation.
Methods

Intrahepatic CD14+ myeloid cells from healthy donors (n = 19) and patients with viral-related liver cirrhosis (HBV, HBV/HDV or HCV; n = 15) were subjected to detailed phenotypic, molecular and functional characterisation.
Results

Unsupervised analysis of multi-parametric data showed that liver disease was associated with the intrahepatic expansion of activated myeloid cells mainly composed of pro-inflammatory CD14+HLA-DRhiCD206+ cells, which spontaneously produced TNFα and GM-CSF. These cells only showed heightened pro-inflammatory responses to bacterial TLR agonists and were more refractory to endotoxin-induced tolerance. A liver-specific enrichment of CD14+HLA-DRhiCD206+ cells was also detected in a humanised mouse model of liver inflammation. This accumulation was abrogated following oral antibiotic treatment, suggesting a direct involvement of translocated gut-derived microbial products in liver injury.
Conclusions

Viral-related chronic liver inflammation is driven by the interplay between non-endotoxin-tolerant pro-inflammatory CD14+HLA-DRhiCD206+ myeloid cells and translocated bacterial products. Deciphering this mechanism paves the way for the development of therapeutic strategies specifically targeting CD206+ myeloid cells in viral-related liver disease patients.

Lay summary: Viral-related chronic liver disease is driven by intrahepatic pro-inflammatory myeloid cells accumulating in a gut-derived bacterial product-dependent manner. Our findings support the use of oral antibiotics to ameliorate liver inflammation in these patients.
Keywords:
Liver inflammation, Bacterial translocation, Viral hepatitis, Monocyte/macrophage, Endotoxin tolerance

StephenW

肝内CD206 +巨噬细胞在晚期病毒相关肝脏疾病中有助于炎症
阿方索谭加西亚
陆仁伟†
郑大海
，Erica Ceccarello
，Juandy Jo
，Nasirah Banu
，Atefeh Khakpoor
，Adeline Chia
，Christine Y.L.谭
，安东尼·坦
，米歇尔·洪
，唐达。
，劳拉里维诺诺
开启谭
康熙李
，盛吉林
，Evan W. Newell
诺曼·帕维尔卡（Norman Pavelka）
陈金淼
，Florent Ginhoux
陈庆丰‡
，Antonio Bertoletti‡
，Charles-Antoine Dutertre关于作者Charles-Antoine Dutertre的信函‡，作者电子邮件Charles-Antoine Dutertre
†这些第一作者对这项工作做出了同样的贡献。
‡这项工作的高级作者。
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DOI：http://dx.doi.org/10.1016/j.jhep.2017.04.023 |

强调

    •肝脏CD14 + HLA-DRhiCD206 +细胞积累在慢性病毒相关性肝病中。
    •CD14 + HLA-DRhiCD206 +细胞是促炎症的并且耐LPS耐受。
    •肠道微生物群影响促炎CD14 + HLA-DRhiCD206 +细胞的积累。

背景与目标

肝脏炎症是慢性病毒性肝炎进展为肝硬化和肝细胞癌的关键。病毒复制的大小和具体的抗病毒免疫应答应该控制炎症的程度，但慢性病毒性肝炎患者中并不总是发现直接的相关性。我们的目标是更好地界定有助于慢性肝炎的机制。
方法

来自健康供体（n = 19）和病毒相关性肝硬化（HBV，HBV / HDV或HCV; n = 15）的肝内CD14 +骨髓细胞进行详细的表型，分子和功能表征。
结果

多参数数据的无监督分析表明，肝脏疾病与主要由促炎CD14 + HLA-DRhiCD206 +细胞组成的活化骨髓细胞肝内扩张相关，其自发产生TNFα和GM-CSF。这些细胞仅显示对细菌TLR激动剂的增强的促炎反应，并且对内毒素诱导的耐受性更难治。在肝脏炎症的人源化小鼠模型中也检测到CD14 + HLA-DRhiCD206 +细胞的肝特异性富集。这种积累在口服抗生素治疗后被废除，表明易位的肠道衍生的微生物产品直接参与肝损伤。
结论

病毒相关的慢性肝脏炎症是由非内毒素耐受性促炎症CD14 + HLA-DRhiCD206 +骨髓细胞和易位细菌产物之间的相互作用驱动的。破译这种机制为病毒相关肝病患者特异性靶向CD206 +骨髓细胞的治疗策略的开发铺平了道路。

摘要：病毒相关的慢性肝病是由肝内促炎骨髓细胞以肠道来源的细菌产物依赖的方式积累的。我们的研究结果支持使用口服抗生素来改善这些患者的肝脏炎症。
关键词：
肝脏炎症，细菌易位，病毒性肝炎，单核细胞/巨噬细胞，内毒素耐受