P09 Prof. Dr. Tacke
Monocyte and macrophage subsets in liver fibrogenesis

Sustained inflammation upon chronic liver injury induces the development of fibrosis. Using mouse models and human samples, we investigate functional contributions of monocyte/ macrophage subpopulations in the progression and regression of liver fibrosis and explore novel strategies for targeting monocyte/macrophage subsets in hepatic fibrogenesis for future therapeutic approaches.

Liver fibrosis as a response to chronic injury is mainly driven by persistent inflammation in the liver. Hepatic macrophages are a critical component in injured liver for inflammation, fibrosis and angiogenesis, but also capable of promoting fibrosis resolution. In our project, we have identified distinct contributions of resident macrophages, termed Kupffer cells, as well as infiltrating monocyte-derived macrophages during liver fibrosis progression and regression. For instance, the chemokine receptor CCR2 and its ligand MCP-1 (CCL2) promote inflammatory monocyte subset infiltration into the liver in mouse models. We have established an intravital multiphoton microscopy-based imaging of mouse livers, which allows monitoring the infiltration of monocyte/macrophage subsets in animal models of liver fibrosis in vivo. Our interventional studies from mice by inhibiting monocyte infiltration during hepatofibrogenesis are now being tested in a phase II clinical trial (Centaur trial, national coordinator: Frank Tacke) with the CCR2/CCR5 inhibitor cenicriviroc for the treatment of non-alcoholic steatohepatitis and fibrosis.  

Important research questions in our project are:

  • Relevance of resident macrophages (Kupffer cells) vs. infiltrating monocyte-derived macrophages in liver homeostasis and disease
  • Molecular factors promoting the recruitment of monocytes (e.g., chemokines)
  • Molecular factor determining the differentiation of macrophages subsets during progression or regression of fibrosis
  • Interactions of macrophage subsets with other hepatic cells (e.g., collagen-producing stellate cells) or other immune cells (e.g., NKT cells)
  • Functions of hepatic macrophage subsets in the progression or regression of fibrosis
  • Therapeutic targeting of monocyte/macrophage subsets in healthy and fibrotic livers
  • Translation of findings from mouse models into human pathogenesis, especially definition of macrophage subpopulations in healthy and fibrotic human liver

This project aims at delineating the functional contributions of different monocyte/ macrophage subpopulations in the progression and regression of liver fibrosis in mice and men, defining the molecular and cellular interactions determining macrophage functionality in fibrosis and exploring novel strategies for targeting monocyte/macrophage populations in hepatic fibrogenesis for future therapeutic approaches.

Publications