Monocytes and Macrophages as Cellular Targets in Liver Fibrosis
Although chronic liver disease has many etiologies, including chronic viral hepatitis, alcohol abuse, metabolic syndrome, and autoimmune disorders, the cellular and pathological mechanisms leading to hepatic fibrosis and – as an end-stage – cirrhosis are relatively common and uniform. Liver fibrosis is characterized by an accumulation of extracellular matrix proteins, and activated hepatic stellate cells (HSC), portal fibroblasts and myofibroblasts have been identified as major collagen-producing cells in the injured liver. Experimental models of liver fibrosis highlight the importance of hepatic macrophages, so-called Kupffer cells, for perpetuating an inflammatory phase resulting in the massive release of proinflammatory cytokines and chemokines as well as activation of HSC. Recent studies demonstrate that these actions are only partially conducted by liver-resident macrophages, but largely depend on recruitment of monocytes into the liver, namely of the inflammatory Gr1+ (Ly6C+) monocyte subset as precursors of tissue macrophages. The chemokine receptor CCR2 and its ligand MCP-1/CCL2 participate in regulating monocyte subset infiltration. Macrophages, on the other hand, display a remarkable plasticity and can differentiate into functionally diverse subtypes, e.g. ‘classically activated’ M1 and ‘alternatively activated’ M2 macrophages. Experimental animal models indicate that monocytes/macrophages are not only critical for fibrosis progression, but also for fibrosis regression, because macrophages can also degrade extracellular matrix proteins and exert anti-inflammatory actions. The recently identified cellular and molecular pathways for monocyte subset recruitment, macrophage differentiation and interactions with other hepatic cell types in the injured liver may therefore represent interesting novel targets for future therapeutic approaches in liver fibrosis.
Keywords: Monocyte, liver fibrosis, macrophage, Kupffer cell, chemokines, CCR2, TGF-β, liver cirrhosis
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