Centenary Institute of Cancer Medicine and Cell Biology, The University of Sydney, NSW, Australia.
Gastroenterology and Liver Laboratory, Ingham Institute for Applied Medical Research, Liverpool, NSW, Australia.
PLoS One. 2019 Jul 10;14(7):e0215557. doi: 10.1371/journal.pone.0215557. eCollection 2019.
Chronic inflammation is the driver of liver injury and results in progressive fibrosis and eventual cirrhosis with consequences including both liver failure and liver cancer. We have previously described increased expression of the highly multifunctional glycoprotein CD147 in liver injury. This work describes a novel role of CD147 in liver inflammation and the importance of leukocyte aggregates in determining the extent of liver injury.
Non-diseased, progressive injury, and cirrhotic liver from humans and mice were examined using a mAb targeting CD147. Inflammatory cell subsets were assessed by multiparameter flow cytometry.
In liver injury, we observe abundant, intrahepatic leukocyte clusters defined as ≥5 adjacent CD45+ cells which we have termed "leukocyte aggregates". We have shown that these leukocyte aggregates have a significant effect in determining the extent of liver injury. If CD147 is blocked in vivo, these leukocyte aggregates diminish in size and number, together with a marked significant reduction in liver injury including fibrosis. This is accompanied by no change in overall intrahepatic leukocyte numbers. Further, blocking of aggregation formation occurs prior to an appreciable increase in inflammatory markers or fibrosis. Additionally, there were no observed, "off-target" or unpredicted effects in targeting CD147.
CD147 mediates leukocyte aggregation which is associated with the development of liver injury. This is not a secondary effect, but a cause of injury as aggregate formation proceeds other markers of injury. Leukocyte aggregation has been previously described in inflammation dating back over many decades. Here we demonstrate that leukocyte aggregates determine the extent of liver injury.
慢性炎症是肝损伤的驱动因素，导致进行性纤维化，最终发展为肝硬化，其后果包括肝衰竭和肝癌。我们之前描述了多功能糖蛋白 CD147 在肝损伤中的表达增加。这项工作描述了 CD147 在肝脏炎症中的一个新作用，以及白细胞聚集在决定肝损伤程度方面的重要性。
使用针对 CD147 的单克隆抗体检查非疾病、进行性损伤和肝硬化的人类和小鼠肝脏。通过多参数流式细胞术评估炎症细胞亚群。
在肝损伤中，我们观察到大量的肝内白细胞簇，定义为≥5 个相邻的 CD45+细胞，我们称之为“白细胞聚集”。我们已经表明，这些白细胞聚集对确定肝损伤的程度有重要影响。如果在体内阻断 CD147，这些白细胞聚集的大小和数量都会减少，同时肝损伤包括纤维化也会显著减少。这伴随着肝内白细胞总数没有变化。此外，聚集形成的阻断发生在炎症标志物或纤维化明显增加之前。此外，靶向 CD147 没有观察到“脱靶”或意外的效果。
CD147 介导白细胞聚集，与肝损伤的发展有关。这不是继发效应，而是损伤的原因，因为聚集形成先于其他损伤标志物。白细胞聚集在炎症中已经被描述了几十年。在这里，我们证明了白细胞聚集决定了肝损伤的程度。
