Program in Emerging Infectious Diseases, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore.
Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (A*STAR), Brenner Centre for Molecular Medicine, 30 Medical Drive, Singapore 117609, Singapore.
J Hepatol. 2017 Sep;67(3):490-500. doi: 10.1016/j.jhep.2017.04.023. Epub 2017 May 5.
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.
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.
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 CD14HLA-DRCD206 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 CD14HLA-DRCD206 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.
Viral-related chronic liver inflammation is driven by the interplay between non-endotoxin-tolerant pro-inflammatory CD14HLA-DRCD206 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.
肝脏炎症是慢性病毒性肝炎发展为肝硬化和肝细胞癌的关键。病毒复制的程度和特定的抗病毒免疫反应应该控制炎症的程度，但在慢性病毒性肝炎患者中并不总是发现直接的相关性。我们旨在更好地定义导致慢性肝脏炎症的机制。
来自健康供体（n=19）和病毒性相关肝硬化患者（HBV、HBV/HDV 或 HCV；n=15）的肝内 CD14 髓样细胞进行了详细的表型、分子和功能特征分析。
未经监督的多参数数据分析表明，肝脏疾病与肝内激活的髓样细胞的扩张有关，这些细胞主要由促炎 CD14HLA-DRCD206 细胞组成，这些细胞自发产生 TNFα 和 GM-CSF。这些细胞仅对细菌 TLR 激动剂表现出更高的促炎反应，并且对内毒素诱导的耐受更具抗性。在人类肝脏炎症的人源化小鼠模型中也检测到 CD14HLA-DRCD206 细胞的肝脏特异性富集。这种积累在口服抗生素治疗后被消除，表明肠道来源的微生物产物的移位直接参与了肝脏损伤。
病毒相关的慢性肝脏炎症是由非内毒素耐受的促炎 CD14HLA-DRCD206 髓样细胞与移位的细菌产物之间的相互作用驱动的。解析这种机制为开发针对病毒相关肝病患者的 CD206 髓样细胞的治疗策略铺平了道路。
非专业人士，仅供参考。
