Figure 4

Representative example of the complexity of the chemokine network regulating immune mechanisms during liver fibrosis. Sophisticated experimental mouse models of chronic injury and fibrosis revealed the complex interplay of different hepatic cells and monocytes/macrophages during hepatofibrogenesis. Injury to the liver induces the expression and release of various chemokines (for example, chemokine (C-C motif) ligand 2 (CCL2), CCL1 and chemokine (C-X3-C motif) ligand 1 (CX₃CL1)) from different hepatic cell subpopulations (for example, hepatocytes, sinusoidal endothelial cells, hepatic stellate cells (HSCs)). These chemokines potently chemoattract inflammatory Ly-6C-expressing monocytes from the circulation. As a consequence, these cells infiltrate the liver parenchyma, and monocytes differentiate into distinct macrophage subsets. Macrophages are a source of profibrogenic transforming growth factor β (TGF-β) that triggers transdifferentiation of HSCs into myofibroblasts (MFBs) responsible for excessive matrix formation and deposition (for example, collagen). On the other hand, macrophages also produce inflammatory cytokines (for example, tumour necrosis factor α (TNF-α), interleukin 1β (IL-1β) and IL-6) that altogether drive apoptosis and steatosis of parenchymal cells (that is, hepatocytes). ECM, extracellular matrix.