Limits...
Functional role of monocytes and macrophages for the inflammatory response in acute liver injury.

Zimmermann HW, Trautwein C, Tacke F - Front Physiol (2012)

Bottom Line: Excessive cell death of hepatocytes in the liver is known to result in a strong hepatic inflammation.Many of these proinflammatory mediators can trigger hepatocytic cell death pathways, e.g., via caspase activation, but also activate protective signaling pathways, e.g., via nuclear factor kappa B (NF-κB).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 ALF.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine III, RWTH-University Hospital Aachen Aachen, Germany.

ABSTRACT
Different etiologies such as drug toxicity, acute viral hepatitis B, or acetaminophen poisoning can cause acute liver injury or even acute liver failure (ALF). Excessive cell death of hepatocytes in the liver is known to result in a strong hepatic inflammation. Experimental murine models of liver injury highlighted the importance of hepatic macrophages, so-called Kupffer cells, for initiating and driving this inflammatory response by releasing proinflammatory cytokines and chemokines including tumor necrosis factor (TNF), interleukin-6 (IL-6), IL-1beta, or monocyte-chemoattractant protein-1 (MCP-1, CCL2) as well as activating other non-parenchymal liver cells, e.g., endothelial or hepatic stellate cells. Many of these proinflammatory mediators can trigger hepatocytic cell death pathways, e.g., via caspase activation, but also activate protective signaling pathways, e.g., via nuclear factor kappa B (NF-κB). Recent studies in mice demonstrated that these macrophage actions largely depend on the recruitment of monocytes into the liver, namely of the inflammatory Ly6c+ (Gr1+) monocyte subset as precursors of tissue macrophages. The chemokine receptor CCR2 and its ligand MCP-1/CCL2 promote monocyte subset infiltration upon liver injury. In contrast, the chemokine receptor CX3CR1 and its ligand fractalkine (CX3CL1) are important negative regulators of monocyte infiltration by controlling their survival and differentiation into functionally diverse macrophage subsets upon injury. 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 ALF.

No MeSH data available.


Related in: MedlinePlus

Development and features of murine and human monocyte subsets. Monocyte development from a common myeloid progenitor (CMP) occurs in the bone-marrow under the control of M-CSF and IL-34 and increasing lineage commitment. A macrophage dendritic progenitor (MDP) gives rise to Ly6chi monocytes and probably also to Ly6clo monocytes. Bone-marrow egress is directed by CCR2, maybe also by other pathways such as CXCR4/CXCL12 (not depicted). Peripheral Ly6chi can shuttle back to the bone-marrow and possibly transdifferentiate into Ly6clo monocytes, a process that might also occur in the periphery (e.g., in the spleen). Murine monocyte subsets constantly express F4/80 and CD11b. Classical Ly6chi are characterized by high expression of CCR2 but only moderate levels of the fractalkine receptor CX3CR1. Furthermore, they express several scavenger receptors (e.g., CD32), selectin ligand CD62L, and the integrin VLA-2. Ly6chi monocytes have a proinflammatory profile since they secrete inflammatory cytokines, migrate into inflamed tissue and give rise to inflammatory macrophages (sharing qualities with classical M1 macrophages), and DC subsets. Ly6clo are less abundant in the periphery and express high CX3CR1, CD86, and LFA-1 whereas CCR2 is almost absent. They patrol blood vessels by crawling across endothelium. During inflammation they can rapidly or protracted enter tissue and presumably develop into macrophages with a rather anti-inflammatory phenotype eliciting wound repair (reminiscent of M2 macrophages). In homeostasis they are currently designated as precursor cells of local macrophages and dendritic cells. Importantly, Ly6Chi derived macrophages can very likely also acquire anti-inflammatory phenotypes in peripheral tissues such as the liver. Intermediate Ly6cint are not depicted here. FACS dot plot in the right upper corner illustrates characteristic distribution of human monocyte subsets. CCR2 high expressing CD14++CD16− monocytes are termed classical monocytes, representing the vast majority of circulating monocytes. Despite phenotypic homology to murine inflammatory Ly6chi monocytes they release immune suppressive IL-10 upon LPS stimulation. In turn, intermediate and non-classical monocytes that are defined by the expression of CD16, display moderate to high CX3CR1 and varying density of CD14 and are far less abundant, but release various inflammatory cytokines after challenge with TLR4 and TLR7 agonists. These functions sharply contrast the rather anti-inflammatory phenotype of Ly6clo monocytes as their putative murine counterparts. Intermediate monocytes and classical monocytes have a distinct surface protein profile (e.g., CCR5 is almost exclusively expressed on the intermediate subset) though functional differences are not fully defined. Abbreviations: CMP, common myeloid progenitor; GMP, granulocyte myeloid progenitor; IFNg, interferon gamma; LFA-1, lymphocyte function antigen 1; M-CSF, macrophage colony-stimulating factor; MDP, macrophage dendritic cell progenitor; NO, nitric oxide; TipDCs, TNF–iNOS-producing dendritic cells; VLA-2, very late antigen 2.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3475871&req=5

Figure 3: Development and features of murine and human monocyte subsets. Monocyte development from a common myeloid progenitor (CMP) occurs in the bone-marrow under the control of M-CSF and IL-34 and increasing lineage commitment. A macrophage dendritic progenitor (MDP) gives rise to Ly6chi monocytes and probably also to Ly6clo monocytes. Bone-marrow egress is directed by CCR2, maybe also by other pathways such as CXCR4/CXCL12 (not depicted). Peripheral Ly6chi can shuttle back to the bone-marrow and possibly transdifferentiate into Ly6clo monocytes, a process that might also occur in the periphery (e.g., in the spleen). Murine monocyte subsets constantly express F4/80 and CD11b. Classical Ly6chi are characterized by high expression of CCR2 but only moderate levels of the fractalkine receptor CX3CR1. Furthermore, they express several scavenger receptors (e.g., CD32), selectin ligand CD62L, and the integrin VLA-2. Ly6chi monocytes have a proinflammatory profile since they secrete inflammatory cytokines, migrate into inflamed tissue and give rise to inflammatory macrophages (sharing qualities with classical M1 macrophages), and DC subsets. Ly6clo are less abundant in the periphery and express high CX3CR1, CD86, and LFA-1 whereas CCR2 is almost absent. They patrol blood vessels by crawling across endothelium. During inflammation they can rapidly or protracted enter tissue and presumably develop into macrophages with a rather anti-inflammatory phenotype eliciting wound repair (reminiscent of M2 macrophages). In homeostasis they are currently designated as precursor cells of local macrophages and dendritic cells. Importantly, Ly6Chi derived macrophages can very likely also acquire anti-inflammatory phenotypes in peripheral tissues such as the liver. Intermediate Ly6cint are not depicted here. FACS dot plot in the right upper corner illustrates characteristic distribution of human monocyte subsets. CCR2 high expressing CD14++CD16− monocytes are termed classical monocytes, representing the vast majority of circulating monocytes. Despite phenotypic homology to murine inflammatory Ly6chi monocytes they release immune suppressive IL-10 upon LPS stimulation. In turn, intermediate and non-classical monocytes that are defined by the expression of CD16, display moderate to high CX3CR1 and varying density of CD14 and are far less abundant, but release various inflammatory cytokines after challenge with TLR4 and TLR7 agonists. These functions sharply contrast the rather anti-inflammatory phenotype of Ly6clo monocytes as their putative murine counterparts. Intermediate monocytes and classical monocytes have a distinct surface protein profile (e.g., CCR5 is almost exclusively expressed on the intermediate subset) though functional differences are not fully defined. Abbreviations: CMP, common myeloid progenitor; GMP, granulocyte myeloid progenitor; IFNg, interferon gamma; LFA-1, lymphocyte function antigen 1; M-CSF, macrophage colony-stimulating factor; MDP, macrophage dendritic cell progenitor; NO, nitric oxide; TipDCs, TNF–iNOS-producing dendritic cells; VLA-2, very late antigen 2.

Mentions: Monocytes circulate in blood vessels, spleen, and bone-marrow (Geissmann et al., 2010). Their development entails several precursor cells ranging from a pluripotent hematopoietic stem cell over a common myeloid (CMP) to a macrophage/DC progenitor (MDP) along a path of rising lineage restriction and commitment encompassing additional intermediate stages (Robbins and Swirski, 2010). This process is under control of the growth factors Csf-1 (alternatively termed M-CSF; Kawasaki et al., 1985) and IL-34 (Lin et al., 2008) that both bind to Csf-1R (M-CSFR/CD115; Wei et al., 2010) and synergistically govern monocyte differentiation in a non-redundant manner (Geissmann et al., 2008). CMPs are referred to as Lin−Sca−IL-7Ra−CD117lowCD34+CD16+ cells that exhibit CD115 and CX3CR1 on their surface and differentiate into macrophages, DCs, and monocytes but not into granulocytes (Akashi et al., 2000; Fogg et al., 2006; Varol et al., 2007). Development from MDP into monocytes occurs in the bone-marrow as the last step of monocyte differentiation before they exit into circulation. This event that is mainly directed by CCR2/CCL2 interactions (especially upon systemic inflammation), but may involve other homeostatic pathways such as CXCR4/CXCL12 (Serbina and Pamer, 2006; Geissmann et al., 2008; Figure 3). The prevalent paradigm of the bone-marrow as the sole source of monocytes, however, has been challenged by more recent investigations. According to these findings, a certain fraction of circulating monocytes delineates from a splenic reservoir in the cords in the subcapsular red pulp and does not require CCR2 signals to enter systemic circulation (Swirski et al., 2009). In fact, release from the splenic site relies on factors including angiotensin II (Swirski et al., 2009). Concordantly, angiotensin-II-lowering agents like angiotensin-converting-enzyme inhibitors confined the mobilization of splenic monocytes in a model of myocardial infarction (Leuschner et al., 2010). CCR2-independent non-medullar monocyte resources therefore have to be incorporated in further studies dedicated to intervene at monocyte allocation in pathological settings.


Functional role of monocytes and macrophages for the inflammatory response in acute liver injury.

Zimmermann HW, Trautwein C, Tacke F - Front Physiol (2012)

Development and features of murine and human monocyte subsets. Monocyte development from a common myeloid progenitor (CMP) occurs in the bone-marrow under the control of M-CSF and IL-34 and increasing lineage commitment. A macrophage dendritic progenitor (MDP) gives rise to Ly6chi monocytes and probably also to Ly6clo monocytes. Bone-marrow egress is directed by CCR2, maybe also by other pathways such as CXCR4/CXCL12 (not depicted). Peripheral Ly6chi can shuttle back to the bone-marrow and possibly transdifferentiate into Ly6clo monocytes, a process that might also occur in the periphery (e.g., in the spleen). Murine monocyte subsets constantly express F4/80 and CD11b. Classical Ly6chi are characterized by high expression of CCR2 but only moderate levels of the fractalkine receptor CX3CR1. Furthermore, they express several scavenger receptors (e.g., CD32), selectin ligand CD62L, and the integrin VLA-2. Ly6chi monocytes have a proinflammatory profile since they secrete inflammatory cytokines, migrate into inflamed tissue and give rise to inflammatory macrophages (sharing qualities with classical M1 macrophages), and DC subsets. Ly6clo are less abundant in the periphery and express high CX3CR1, CD86, and LFA-1 whereas CCR2 is almost absent. They patrol blood vessels by crawling across endothelium. During inflammation they can rapidly or protracted enter tissue and presumably develop into macrophages with a rather anti-inflammatory phenotype eliciting wound repair (reminiscent of M2 macrophages). In homeostasis they are currently designated as precursor cells of local macrophages and dendritic cells. Importantly, Ly6Chi derived macrophages can very likely also acquire anti-inflammatory phenotypes in peripheral tissues such as the liver. Intermediate Ly6cint are not depicted here. FACS dot plot in the right upper corner illustrates characteristic distribution of human monocyte subsets. CCR2 high expressing CD14++CD16− monocytes are termed classical monocytes, representing the vast majority of circulating monocytes. Despite phenotypic homology to murine inflammatory Ly6chi monocytes they release immune suppressive IL-10 upon LPS stimulation. In turn, intermediate and non-classical monocytes that are defined by the expression of CD16, display moderate to high CX3CR1 and varying density of CD14 and are far less abundant, but release various inflammatory cytokines after challenge with TLR4 and TLR7 agonists. These functions sharply contrast the rather anti-inflammatory phenotype of Ly6clo monocytes as their putative murine counterparts. Intermediate monocytes and classical monocytes have a distinct surface protein profile (e.g., CCR5 is almost exclusively expressed on the intermediate subset) though functional differences are not fully defined. Abbreviations: CMP, common myeloid progenitor; GMP, granulocyte myeloid progenitor; IFNg, interferon gamma; LFA-1, lymphocyte function antigen 1; M-CSF, macrophage colony-stimulating factor; MDP, macrophage dendritic cell progenitor; NO, nitric oxide; TipDCs, TNF–iNOS-producing dendritic cells; VLA-2, very late antigen 2.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3475871&req=5

Figure 3: Development and features of murine and human monocyte subsets. Monocyte development from a common myeloid progenitor (CMP) occurs in the bone-marrow under the control of M-CSF and IL-34 and increasing lineage commitment. A macrophage dendritic progenitor (MDP) gives rise to Ly6chi monocytes and probably also to Ly6clo monocytes. Bone-marrow egress is directed by CCR2, maybe also by other pathways such as CXCR4/CXCL12 (not depicted). Peripheral Ly6chi can shuttle back to the bone-marrow and possibly transdifferentiate into Ly6clo monocytes, a process that might also occur in the periphery (e.g., in the spleen). Murine monocyte subsets constantly express F4/80 and CD11b. Classical Ly6chi are characterized by high expression of CCR2 but only moderate levels of the fractalkine receptor CX3CR1. Furthermore, they express several scavenger receptors (e.g., CD32), selectin ligand CD62L, and the integrin VLA-2. Ly6chi monocytes have a proinflammatory profile since they secrete inflammatory cytokines, migrate into inflamed tissue and give rise to inflammatory macrophages (sharing qualities with classical M1 macrophages), and DC subsets. Ly6clo are less abundant in the periphery and express high CX3CR1, CD86, and LFA-1 whereas CCR2 is almost absent. They patrol blood vessels by crawling across endothelium. During inflammation they can rapidly or protracted enter tissue and presumably develop into macrophages with a rather anti-inflammatory phenotype eliciting wound repair (reminiscent of M2 macrophages). In homeostasis they are currently designated as precursor cells of local macrophages and dendritic cells. Importantly, Ly6Chi derived macrophages can very likely also acquire anti-inflammatory phenotypes in peripheral tissues such as the liver. Intermediate Ly6cint are not depicted here. FACS dot plot in the right upper corner illustrates characteristic distribution of human monocyte subsets. CCR2 high expressing CD14++CD16− monocytes are termed classical monocytes, representing the vast majority of circulating monocytes. Despite phenotypic homology to murine inflammatory Ly6chi monocytes they release immune suppressive IL-10 upon LPS stimulation. In turn, intermediate and non-classical monocytes that are defined by the expression of CD16, display moderate to high CX3CR1 and varying density of CD14 and are far less abundant, but release various inflammatory cytokines after challenge with TLR4 and TLR7 agonists. These functions sharply contrast the rather anti-inflammatory phenotype of Ly6clo monocytes as their putative murine counterparts. Intermediate monocytes and classical monocytes have a distinct surface protein profile (e.g., CCR5 is almost exclusively expressed on the intermediate subset) though functional differences are not fully defined. Abbreviations: CMP, common myeloid progenitor; GMP, granulocyte myeloid progenitor; IFNg, interferon gamma; LFA-1, lymphocyte function antigen 1; M-CSF, macrophage colony-stimulating factor; MDP, macrophage dendritic cell progenitor; NO, nitric oxide; TipDCs, TNF–iNOS-producing dendritic cells; VLA-2, very late antigen 2.
Mentions: Monocytes circulate in blood vessels, spleen, and bone-marrow (Geissmann et al., 2010). Their development entails several precursor cells ranging from a pluripotent hematopoietic stem cell over a common myeloid (CMP) to a macrophage/DC progenitor (MDP) along a path of rising lineage restriction and commitment encompassing additional intermediate stages (Robbins and Swirski, 2010). This process is under control of the growth factors Csf-1 (alternatively termed M-CSF; Kawasaki et al., 1985) and IL-34 (Lin et al., 2008) that both bind to Csf-1R (M-CSFR/CD115; Wei et al., 2010) and synergistically govern monocyte differentiation in a non-redundant manner (Geissmann et al., 2008). CMPs are referred to as Lin−Sca−IL-7Ra−CD117lowCD34+CD16+ cells that exhibit CD115 and CX3CR1 on their surface and differentiate into macrophages, DCs, and monocytes but not into granulocytes (Akashi et al., 2000; Fogg et al., 2006; Varol et al., 2007). Development from MDP into monocytes occurs in the bone-marrow as the last step of monocyte differentiation before they exit into circulation. This event that is mainly directed by CCR2/CCL2 interactions (especially upon systemic inflammation), but may involve other homeostatic pathways such as CXCR4/CXCL12 (Serbina and Pamer, 2006; Geissmann et al., 2008; Figure 3). The prevalent paradigm of the bone-marrow as the sole source of monocytes, however, has been challenged by more recent investigations. According to these findings, a certain fraction of circulating monocytes delineates from a splenic reservoir in the cords in the subcapsular red pulp and does not require CCR2 signals to enter systemic circulation (Swirski et al., 2009). In fact, release from the splenic site relies on factors including angiotensin II (Swirski et al., 2009). Concordantly, angiotensin-II-lowering agents like angiotensin-converting-enzyme inhibitors confined the mobilization of splenic monocytes in a model of myocardial infarction (Leuschner et al., 2010). CCR2-independent non-medullar monocyte resources therefore have to be incorporated in further studies dedicated to intervene at monocyte allocation in pathological settings.

Bottom Line: Excessive cell death of hepatocytes in the liver is known to result in a strong hepatic inflammation.Many of these proinflammatory mediators can trigger hepatocytic cell death pathways, e.g., via caspase activation, but also activate protective signaling pathways, e.g., via nuclear factor kappa B (NF-κB).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 ALF.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine III, RWTH-University Hospital Aachen Aachen, Germany.

ABSTRACT
Different etiologies such as drug toxicity, acute viral hepatitis B, or acetaminophen poisoning can cause acute liver injury or even acute liver failure (ALF). Excessive cell death of hepatocytes in the liver is known to result in a strong hepatic inflammation. Experimental murine models of liver injury highlighted the importance of hepatic macrophages, so-called Kupffer cells, for initiating and driving this inflammatory response by releasing proinflammatory cytokines and chemokines including tumor necrosis factor (TNF), interleukin-6 (IL-6), IL-1beta, or monocyte-chemoattractant protein-1 (MCP-1, CCL2) as well as activating other non-parenchymal liver cells, e.g., endothelial or hepatic stellate cells. Many of these proinflammatory mediators can trigger hepatocytic cell death pathways, e.g., via caspase activation, but also activate protective signaling pathways, e.g., via nuclear factor kappa B (NF-κB). Recent studies in mice demonstrated that these macrophage actions largely depend on the recruitment of monocytes into the liver, namely of the inflammatory Ly6c+ (Gr1+) monocyte subset as precursors of tissue macrophages. The chemokine receptor CCR2 and its ligand MCP-1/CCL2 promote monocyte subset infiltration upon liver injury. In contrast, the chemokine receptor CX3CR1 and its ligand fractalkine (CX3CL1) are important negative regulators of monocyte infiltration by controlling their survival and differentiation into functionally diverse macrophage subsets upon injury. 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 ALF.

No MeSH data available.


Related in: MedlinePlus