Abstract
BackgroundChronic 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.MethodsNon-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.ResultsIn 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.ConclusionCD147 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.
Highlights
The classical hallmark of liver injury is the deposition of abnormal/fibrotic extracellular matrix (ECM) and the eventual development of cirrhosis, which is mediated by the activated hepatic stellate cell (HSC)
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
CD147 mediates leukocyte aggregation which is associated with the development of liver injury
Summary
The classical hallmark of liver injury is the deposition of abnormal/fibrotic extracellular matrix (ECM) and the eventual development of cirrhosis, which is mediated by the activated hepatic stellate cell (HSC). T-cell responses are clearly pivotal to the development of chronic immune-mediated hepatic injury and it has been shown that Bcells are essential for the development of intrahepatic fibrosis leading to cirrhosis [7,8,9,10,11]. We have previously identified a number of novel pathways of liver injury [12,13,14]. Arising from these studies, we have shown that hepatocytes remodel extracellular matrix in liver injury via the production of active matrix-metalloproteinases [15]. This work describes a novel role of CD147 in liver inflammation and the importance of leukocyte aggregates in determining the extent of liver injury.
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