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Functional role of intrahepatic monocyte subsets for the progression of liver inflammation and liver fibrosis in vivo.

Tacke F - Fibrogenesis Tissue Repair (2012)

Bottom Line: Upon organ injury, chemokine receptor CCR2 and its ligand MCP-1 (CCL2) as well as CCR8 and CCL1 promote monocyte subset accumulation in the liver, namely of the inflammatory Ly6C(+) (Gr1(+)) monocyte subset as precursors of tissue macrophages.The infiltration of proinflammatory monocytes into injured murine liver can be specifically blocked by novel anti-MCP-1 directed agents.In patients with liver cirrhosis, 'non-classical' CD14(+)CD16(+) monocytes are found activated in blood as well as liver and promote pro-inflammatory along with pro-fibrogenic actions by the release of distinct cytokines and direct interactions with HSC, indicating that the findings from murine models can be translated into pathogenesis of human liver fibrosis.

View Article: PubMed Central - HTML - PubMed

Affiliation: Dept of Medicine III, University Hospital Aachen, Germany.

ABSTRACT
Sustained inflammation upon chronic liver injury induces the development of liver fibrosis in mice and men. Experimental models of liver fibrosis highlight the importance of hepatic macrophages, so-called Kupffer cells, for perpetuating inflammation by releasing proinflammatory cytokines and chemokines as well as activating hepatic stellate cells (HSC). Recent studies in mice demonstrate that these actions are only partially conducted by liver-resident macrophages, classically termed Kupffer cells, but largely depend on recruitment of monocytes into the liver. Monocytes are circulating precursors of tissue macrophages and dendritic cells (DC), which comprise two major subsets in blood, characterized by the differential expression of chemokine receptors, adhesion molecules and distinct markers, such as Ly6C/Gr1 in mice or CD14 and CD16 in humans. Upon organ injury, chemokine receptor CCR2 and its ligand MCP-1 (CCL2) as well as CCR8 and CCL1 promote monocyte subset accumulation in the liver, namely of the inflammatory Ly6C(+) (Gr1(+)) monocyte subset as precursors of tissue macrophages. The infiltration of proinflammatory monocytes into injured murine liver can be specifically blocked by novel anti-MCP-1 directed agents. In contrast, chemokine receptor CX3CR1 and its ligand fractalkine (CX3CL1) are important negative regulators of monocyte infiltration in hepatic inflammation by controlling their survival and differentiation into functionally diverse macrophage subsets. In patients with liver cirrhosis, 'non-classical' CD14(+)CD16(+) monocytes are found activated in blood as well as liver and promote pro-inflammatory along with pro-fibrogenic actions by the release of distinct cytokines and direct interactions with HSC, indicating that the findings from murine models can be translated into pathogenesis of human liver fibrosis. Moreover, experimental animal models indicate that monocytes/macrophages and DCs 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 injured liver may therefore represent interesting novel targets for future therapeutic approaches in liver fibrosis.

No MeSH data available.


Related in: MedlinePlus

Monocyte subsets in experimental liver fibrosis in mice. Upon liver injury, hepatocytes, hepatic stellate cells, endothelium and resident macrophages (Kupffer cells) release many cytokines and chemokines (not shown in detail). CCL2 is an important mediator that promotes the accumulation of inflammatory CCR2+ Ly6Chi (Gr1hi) monocytes from blood into the injured liver. CCR8 and its ligand CCL1 also promote monocyte/macrophage migration in hepatic fibrosis. Intrahepatic monocytes develop preferentially into 'M1' inflammatory macrophages in this setting. These monocytes/macrophages release proinflammatory cytokines such as TNFα, IL1β or IL6 that further promote hepatocyte apoptosis, hepatocyte steatosis and inflammation, but also directly interact with hepatic stellate cells via TGFβ, thereby contributing to myofibroblast transdifferentiation and collagen production. CX3CL1-CX3CR1 interactions on monocytes/macrophages are anti-inflammatory and anti-fibrotic by prolonging monocyte survival and limiting M1 macrophage differentiation.
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Figure 1: Monocyte subsets in experimental liver fibrosis in mice. Upon liver injury, hepatocytes, hepatic stellate cells, endothelium and resident macrophages (Kupffer cells) release many cytokines and chemokines (not shown in detail). CCL2 is an important mediator that promotes the accumulation of inflammatory CCR2+ Ly6Chi (Gr1hi) monocytes from blood into the injured liver. CCR8 and its ligand CCL1 also promote monocyte/macrophage migration in hepatic fibrosis. Intrahepatic monocytes develop preferentially into 'M1' inflammatory macrophages in this setting. These monocytes/macrophages release proinflammatory cytokines such as TNFα, IL1β or IL6 that further promote hepatocyte apoptosis, hepatocyte steatosis and inflammation, but also directly interact with hepatic stellate cells via TGFβ, thereby contributing to myofibroblast transdifferentiation and collagen production. CX3CL1-CX3CR1 interactions on monocytes/macrophages are anti-inflammatory and anti-fibrotic by prolonging monocyte survival and limiting M1 macrophage differentiation.

Mentions: Because Ly6Chi monocytes express high levels of CCR2 [20] and activated hepatic stellate cells were shown to release high amounts of the CCR2-ligand MCP-1 [39,40], we compared wildtype with CCR2- and CCR2/CCR6-deficient mice in the CCl4 fibrosis model in order to identify possible chemokine receptor pathways mediating monocyte migration into the liver. These experiments revealed that the chemokine receptor CCR2 critically controls intrahepatic Ly6Chi monocyte accumulation, at the level of mediating their egress from the bone marrow. Impaired monocyte subset recruitment in CCR2-/- and CCR2-/-CCR6-/- mice resulted in reduced HSC activation and diminished liver fibrosis. Moreover, adoptively transferred Ly6Chi monocytes traffic into the injured liver and promote fibrosis progression in wildtype and CCR2-/-CCR6-/- mice, which are otherwise protected from hepatic fibrosis. Intrahepatic CD11b+F4/80+Ly6C+ monocyte-derived macrophages purified from CCl4-treated animals, but not 'naïve' bone marrow monocytes or control lymphocytes, directly activate HSC in a TGFβ-dependent manner in vitro [4]. Collectively, these data indicate that inflammatory Ly6C+ monocytes, recruited into the injured liver via CCR2-dependent bone marrow egress, promote the progression of liver fibrosis (Figure 1).


Functional role of intrahepatic monocyte subsets for the progression of liver inflammation and liver fibrosis in vivo.

Tacke F - Fibrogenesis Tissue Repair (2012)

Monocyte subsets in experimental liver fibrosis in mice. Upon liver injury, hepatocytes, hepatic stellate cells, endothelium and resident macrophages (Kupffer cells) release many cytokines and chemokines (not shown in detail). CCL2 is an important mediator that promotes the accumulation of inflammatory CCR2+ Ly6Chi (Gr1hi) monocytes from blood into the injured liver. CCR8 and its ligand CCL1 also promote monocyte/macrophage migration in hepatic fibrosis. Intrahepatic monocytes develop preferentially into 'M1' inflammatory macrophages in this setting. These monocytes/macrophages release proinflammatory cytokines such as TNFα, IL1β or IL6 that further promote hepatocyte apoptosis, hepatocyte steatosis and inflammation, but also directly interact with hepatic stellate cells via TGFβ, thereby contributing to myofibroblast transdifferentiation and collagen production. CX3CL1-CX3CR1 interactions on monocytes/macrophages are anti-inflammatory and anti-fibrotic by prolonging monocyte survival and limiting M1 macrophage differentiation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3368797&req=5

Figure 1: Monocyte subsets in experimental liver fibrosis in mice. Upon liver injury, hepatocytes, hepatic stellate cells, endothelium and resident macrophages (Kupffer cells) release many cytokines and chemokines (not shown in detail). CCL2 is an important mediator that promotes the accumulation of inflammatory CCR2+ Ly6Chi (Gr1hi) monocytes from blood into the injured liver. CCR8 and its ligand CCL1 also promote monocyte/macrophage migration in hepatic fibrosis. Intrahepatic monocytes develop preferentially into 'M1' inflammatory macrophages in this setting. These monocytes/macrophages release proinflammatory cytokines such as TNFα, IL1β or IL6 that further promote hepatocyte apoptosis, hepatocyte steatosis and inflammation, but also directly interact with hepatic stellate cells via TGFβ, thereby contributing to myofibroblast transdifferentiation and collagen production. CX3CL1-CX3CR1 interactions on monocytes/macrophages are anti-inflammatory and anti-fibrotic by prolonging monocyte survival and limiting M1 macrophage differentiation.
Mentions: Because Ly6Chi monocytes express high levels of CCR2 [20] and activated hepatic stellate cells were shown to release high amounts of the CCR2-ligand MCP-1 [39,40], we compared wildtype with CCR2- and CCR2/CCR6-deficient mice in the CCl4 fibrosis model in order to identify possible chemokine receptor pathways mediating monocyte migration into the liver. These experiments revealed that the chemokine receptor CCR2 critically controls intrahepatic Ly6Chi monocyte accumulation, at the level of mediating their egress from the bone marrow. Impaired monocyte subset recruitment in CCR2-/- and CCR2-/-CCR6-/- mice resulted in reduced HSC activation and diminished liver fibrosis. Moreover, adoptively transferred Ly6Chi monocytes traffic into the injured liver and promote fibrosis progression in wildtype and CCR2-/-CCR6-/- mice, which are otherwise protected from hepatic fibrosis. Intrahepatic CD11b+F4/80+Ly6C+ monocyte-derived macrophages purified from CCl4-treated animals, but not 'naïve' bone marrow monocytes or control lymphocytes, directly activate HSC in a TGFβ-dependent manner in vitro [4]. Collectively, these data indicate that inflammatory Ly6C+ monocytes, recruited into the injured liver via CCR2-dependent bone marrow egress, promote the progression of liver fibrosis (Figure 1).

Bottom Line: Upon organ injury, chemokine receptor CCR2 and its ligand MCP-1 (CCL2) as well as CCR8 and CCL1 promote monocyte subset accumulation in the liver, namely of the inflammatory Ly6C(+) (Gr1(+)) monocyte subset as precursors of tissue macrophages.The infiltration of proinflammatory monocytes into injured murine liver can be specifically blocked by novel anti-MCP-1 directed agents.In patients with liver cirrhosis, 'non-classical' CD14(+)CD16(+) monocytes are found activated in blood as well as liver and promote pro-inflammatory along with pro-fibrogenic actions by the release of distinct cytokines and direct interactions with HSC, indicating that the findings from murine models can be translated into pathogenesis of human liver fibrosis.

View Article: PubMed Central - HTML - PubMed

Affiliation: Dept of Medicine III, University Hospital Aachen, Germany.

ABSTRACT
Sustained inflammation upon chronic liver injury induces the development of liver fibrosis in mice and men. Experimental models of liver fibrosis highlight the importance of hepatic macrophages, so-called Kupffer cells, for perpetuating inflammation by releasing proinflammatory cytokines and chemokines as well as activating hepatic stellate cells (HSC). Recent studies in mice demonstrate that these actions are only partially conducted by liver-resident macrophages, classically termed Kupffer cells, but largely depend on recruitment of monocytes into the liver. Monocytes are circulating precursors of tissue macrophages and dendritic cells (DC), which comprise two major subsets in blood, characterized by the differential expression of chemokine receptors, adhesion molecules and distinct markers, such as Ly6C/Gr1 in mice or CD14 and CD16 in humans. Upon organ injury, chemokine receptor CCR2 and its ligand MCP-1 (CCL2) as well as CCR8 and CCL1 promote monocyte subset accumulation in the liver, namely of the inflammatory Ly6C(+) (Gr1(+)) monocyte subset as precursors of tissue macrophages. The infiltration of proinflammatory monocytes into injured murine liver can be specifically blocked by novel anti-MCP-1 directed agents. In contrast, chemokine receptor CX3CR1 and its ligand fractalkine (CX3CL1) are important negative regulators of monocyte infiltration in hepatic inflammation by controlling their survival and differentiation into functionally diverse macrophage subsets. In patients with liver cirrhosis, 'non-classical' CD14(+)CD16(+) monocytes are found activated in blood as well as liver and promote pro-inflammatory along with pro-fibrogenic actions by the release of distinct cytokines and direct interactions with HSC, indicating that the findings from murine models can be translated into pathogenesis of human liver fibrosis. Moreover, experimental animal models indicate that monocytes/macrophages and DCs 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 injured liver may therefore represent interesting novel targets for future therapeutic approaches in liver fibrosis.

No MeSH data available.


Related in: MedlinePlus