Contribution of the platelet receptor CLEC-2 and its ligand podoplanin to the pathogenesis of liver disease

[摘要] Increasing lines of evidence place platelets as having a central role in liver disease. Platelets are recruited to the liver and, depending upon stage and type of liver injury play varying roles ranging from driving liver fibrosis to aiding regeneration. However the molecular basis and consequences of platelet activation in the liver are less clear. The work presented in this thesis demonstrates for the first time that platelet activation via CLEC-2 is important in the pathogenesis of liver disease. In chronic human diseases (CLD) such as Primary Biliary Cirrhosis, and Alcoholic Liver disease I have demonstrated that the ligand for CLEC-2, podoplanin is upregulated on portal venules and increases proportionately to disease activity. I also note podoplanin staining on macrophage populations in CLD. Furthermore I show that this enhanced podoplanin expression may be a useful predictor of portal venous thrombosis, and correlates with MELD score for some categories of disease.In acute liver injury, CLEC-2-depended platelet activation has a profound effect on disease development. Here podoplanin expression occurs upon Kupffer cells in both humans and mice. Using carbon tetrachloride and paracetamol to induce acute liver injury in mice, I show that macrophage-expressed podoplanin activates platelets via CLEC-2. This interaction worsens liver injury, I next show that by blocking this interaction (using either CLEC-2 or podoplanin-deficient mice, or by using a function- blocking podoplanin antibody) liver recovery from toxic liver injury was remarkably enhanced. This was dependent upon enhanced hepatic neutrophil recruitment in a TNF dependent fashion.

[发布机构] University:University of Birmingham;Department:Institute of Immunology and Immunotherapy

[关键词] Q Science;QH Natural history;QH301 Biology