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

Kupffer cell (KC)/Macrophage (MΦ) function during liver homeostasis. Phagocytosis and induction of immune tolerance as the two main functions of KCs/hepatic MΦ in the steady state are depicted here. KCs reside in the liver sinusoids in close proximity to sinusoidal endothelial cells (LSEC) and immune cells entering the liver microvasculature mainly through the portal vein. KCs express a broad range of surface receptors mediating phagocytosis, which renders these cells as highly effective filters of endogenous and exogenous antigens. Complement receptors mediate removal of complement-opsonized material. Circulating non-opsonized immune globulin complexes are cleared through Fc-γ Receptors. Insoluble macromolecules from multiple sources are effectively cleared after binding to Scavenger Receptors including CD163 for senescent erythrocytes. Molecules with a mannosyl motif are phagocytized following engagement of mannose receptors. Engulfment of apoptotic cell constituents can induce secretion of immunosuppressive IL-10 which likely contributes to the immune modulatory function of quiescent KCs. Constant exposure to gut-derived LPS via TLR4 also results in expression of IL-10 and PGE2 that can directly inhibit T-cell and NK-cell function and mediate down-regulation of co-stimulatory proteins including CD80, CD86, and MHC class II on endothelial cells, dendritic cells, and KCs constituting liver APCs, which further attenuates T-cell activation. KC-secreted PD-L1 and release of apoptosis-inducing mediators (TRAIL, FasL) contribute to suppression of adaptive and innate immune response through inactivation/elimination of T-cells and NK-cells. IL-10, PGE2, and TNF-alpha lead to reduced expression of adhesion molecules (VCAM-1; ICAM-1) on LSEC, thereby limiting leukocyte influx. Abbreviations: APC, antigen presenting cell; CR, complement receptor; FasL, Fas ligand; ICAM-1, intercellular adhesion molecule 1; PD-L, programmed cell death 1 ligand 1; PGE2, prostaglandin E2; SR-AI/II, scavenger receptor AI/AII; TLR4, toll-like receptor 4; TRAIL, tumor necrosis factor related apoptosis-inducing ligand; VCAM-1, vascular adhesion molecular 1.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Kupffer cell (KC)/Macrophage (MΦ) function during liver homeostasis. Phagocytosis and induction of immune tolerance as the two main functions of KCs/hepatic MΦ in the steady state are depicted here. KCs reside in the liver sinusoids in close proximity to sinusoidal endothelial cells (LSEC) and immune cells entering the liver microvasculature mainly through the portal vein. KCs express a broad range of surface receptors mediating phagocytosis, which renders these cells as highly effective filters of endogenous and exogenous antigens. Complement receptors mediate removal of complement-opsonized material. Circulating non-opsonized immune globulin complexes are cleared through Fc-γ Receptors. Insoluble macromolecules from multiple sources are effectively cleared after binding to Scavenger Receptors including CD163 for senescent erythrocytes. Molecules with a mannosyl motif are phagocytized following engagement of mannose receptors. Engulfment of apoptotic cell constituents can induce secretion of immunosuppressive IL-10 which likely contributes to the immune modulatory function of quiescent KCs. Constant exposure to gut-derived LPS via TLR4 also results in expression of IL-10 and PGE2 that can directly inhibit T-cell and NK-cell function and mediate down-regulation of co-stimulatory proteins including CD80, CD86, and MHC class II on endothelial cells, dendritic cells, and KCs constituting liver APCs, which further attenuates T-cell activation. KC-secreted PD-L1 and release of apoptosis-inducing mediators (TRAIL, FasL) contribute to suppression of adaptive and innate immune response through inactivation/elimination of T-cells and NK-cells. IL-10, PGE2, and TNF-alpha lead to reduced expression of adhesion molecules (VCAM-1; ICAM-1) on LSEC, thereby limiting leukocyte influx. Abbreviations: APC, antigen presenting cell; CR, complement receptor; FasL, Fas ligand; ICAM-1, intercellular adhesion molecule 1; PD-L, programmed cell death 1 ligand 1; PGE2, prostaglandin E2; SR-AI/II, scavenger receptor AI/AII; TLR4, toll-like receptor 4; TRAIL, tumor necrosis factor related apoptosis-inducing ligand; VCAM-1, vascular adhesion molecular 1.

Mentions: Owing to the direct vascular connection to the splanchnic organs as a source of potential environmental and inherent threats, integral parts of the innate immune system are highly enriched in the liver. This renders the liver as an immunological organ with predominant innate immune functions (Racanelli and Rehermann, 2006; Gao et al., 2008). Apart from resident immune cells that respond to exterior and interior damaging influences, the liver is also source of a host of soluble factors encompassing acute-phase-proteins, complement factors, cytokines, and chemokines, which all contribute to the meticulous orchestration of immune response to various stimuli (Ishibashi et al., 2009). However, the liver is perpetually confronted with harmless nutrient-borne antigens and low levels of LPS and other microbial products. Those do not represent an inflammatory stimulus in steady state conditions but elicit immunosuppressive responses in order to prevent constant detrimental immune activation (Tacke et al., 2009). Intrahepatic macrophages accommodate for both opposing scenarios: promoting immune tolerance during homeostasis as well as implementing proinflammatory mechanisms in acute and chronic liver injury. KCs traditionally denote hepatic (resident) macrophages and represent up to 80–90% of the total body macrophage pool (Ishibashi et al., 2009). Together with LSEC, hepatic stellate cells (HSC), and local immune cells [in particular atypical T-cells, NK-cells (pit cells), and hepatic dendritic cells (DCs)] KCs constitute the non-parenchymal liver cells. They dwell in the lumen of liver sinusoids in close contact to the sinusoidal endothelial cells and sense the circulating blood for food-borne antigens and microbial constituents stemming from the splanchnic circulation. The sinusoidal site also guarantees intimate contact and communication with immune cells that enter the liver via the portal vein. In the non-inflamed liver one of the key functions of KCs is the removal of insoluble macromolecules through phagocytosis mediated by a wide repertoire of pattern-recognition receptors (PRRs) on their surface including scavenger receptors SR-AI and SR-AII, mannose receptor, and Fc-γ receptors (Gao et al., 2008; Figure 1). Thereby, hepatic macrophages eliminate potential harmful threats elicited by degenerated cells, microbes, immune complexes, and toxins (Kolios et al., 2006). KC show functional disparities related to their localization within the liver lobule (Bilzer et al., 2006). Periportal KCs, which are the first macrophages to encounter inflowing portal blood, are more abundant, bigger in size, and exhibit greater phagocytic and lysosomal capacities in addition to an increased production of inflammatory mediators [such as interleukin-1 (IL-1) and tumor necrosis factor (TNF) alpha (TNF-alpha)], in comparison to those hepatic macrophages located in the midzonal area and around the central vein (Sleyster and Knook, 1982; Hoedemakers et al., 1995). Moreover, KCs are not entirely static in the sinusoidal lumen but migrate across the sinusoidal walls and are capable of reducing the sinusoidal blood velocity hence supporting the contact of circulating immune cells with sinusoidal endothelial cells (MacPhee et al., 1992, 1995).


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

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

Kupffer cell (KC)/Macrophage (MΦ) function during liver homeostasis. Phagocytosis and induction of immune tolerance as the two main functions of KCs/hepatic MΦ in the steady state are depicted here. KCs reside in the liver sinusoids in close proximity to sinusoidal endothelial cells (LSEC) and immune cells entering the liver microvasculature mainly through the portal vein. KCs express a broad range of surface receptors mediating phagocytosis, which renders these cells as highly effective filters of endogenous and exogenous antigens. Complement receptors mediate removal of complement-opsonized material. Circulating non-opsonized immune globulin complexes are cleared through Fc-γ Receptors. Insoluble macromolecules from multiple sources are effectively cleared after binding to Scavenger Receptors including CD163 for senescent erythrocytes. Molecules with a mannosyl motif are phagocytized following engagement of mannose receptors. Engulfment of apoptotic cell constituents can induce secretion of immunosuppressive IL-10 which likely contributes to the immune modulatory function of quiescent KCs. Constant exposure to gut-derived LPS via TLR4 also results in expression of IL-10 and PGE2 that can directly inhibit T-cell and NK-cell function and mediate down-regulation of co-stimulatory proteins including CD80, CD86, and MHC class II on endothelial cells, dendritic cells, and KCs constituting liver APCs, which further attenuates T-cell activation. KC-secreted PD-L1 and release of apoptosis-inducing mediators (TRAIL, FasL) contribute to suppression of adaptive and innate immune response through inactivation/elimination of T-cells and NK-cells. IL-10, PGE2, and TNF-alpha lead to reduced expression of adhesion molecules (VCAM-1; ICAM-1) on LSEC, thereby limiting leukocyte influx. Abbreviations: APC, antigen presenting cell; CR, complement receptor; FasL, Fas ligand; ICAM-1, intercellular adhesion molecule 1; PD-L, programmed cell death 1 ligand 1; PGE2, prostaglandin E2; SR-AI/II, scavenger receptor AI/AII; TLR4, toll-like receptor 4; TRAIL, tumor necrosis factor related apoptosis-inducing ligand; VCAM-1, vascular adhesion molecular 1.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Kupffer cell (KC)/Macrophage (MΦ) function during liver homeostasis. Phagocytosis and induction of immune tolerance as the two main functions of KCs/hepatic MΦ in the steady state are depicted here. KCs reside in the liver sinusoids in close proximity to sinusoidal endothelial cells (LSEC) and immune cells entering the liver microvasculature mainly through the portal vein. KCs express a broad range of surface receptors mediating phagocytosis, which renders these cells as highly effective filters of endogenous and exogenous antigens. Complement receptors mediate removal of complement-opsonized material. Circulating non-opsonized immune globulin complexes are cleared through Fc-γ Receptors. Insoluble macromolecules from multiple sources are effectively cleared after binding to Scavenger Receptors including CD163 for senescent erythrocytes. Molecules with a mannosyl motif are phagocytized following engagement of mannose receptors. Engulfment of apoptotic cell constituents can induce secretion of immunosuppressive IL-10 which likely contributes to the immune modulatory function of quiescent KCs. Constant exposure to gut-derived LPS via TLR4 also results in expression of IL-10 and PGE2 that can directly inhibit T-cell and NK-cell function and mediate down-regulation of co-stimulatory proteins including CD80, CD86, and MHC class II on endothelial cells, dendritic cells, and KCs constituting liver APCs, which further attenuates T-cell activation. KC-secreted PD-L1 and release of apoptosis-inducing mediators (TRAIL, FasL) contribute to suppression of adaptive and innate immune response through inactivation/elimination of T-cells and NK-cells. IL-10, PGE2, and TNF-alpha lead to reduced expression of adhesion molecules (VCAM-1; ICAM-1) on LSEC, thereby limiting leukocyte influx. Abbreviations: APC, antigen presenting cell; CR, complement receptor; FasL, Fas ligand; ICAM-1, intercellular adhesion molecule 1; PD-L, programmed cell death 1 ligand 1; PGE2, prostaglandin E2; SR-AI/II, scavenger receptor AI/AII; TLR4, toll-like receptor 4; TRAIL, tumor necrosis factor related apoptosis-inducing ligand; VCAM-1, vascular adhesion molecular 1.
Mentions: Owing to the direct vascular connection to the splanchnic organs as a source of potential environmental and inherent threats, integral parts of the innate immune system are highly enriched in the liver. This renders the liver as an immunological organ with predominant innate immune functions (Racanelli and Rehermann, 2006; Gao et al., 2008). Apart from resident immune cells that respond to exterior and interior damaging influences, the liver is also source of a host of soluble factors encompassing acute-phase-proteins, complement factors, cytokines, and chemokines, which all contribute to the meticulous orchestration of immune response to various stimuli (Ishibashi et al., 2009). However, the liver is perpetually confronted with harmless nutrient-borne antigens and low levels of LPS and other microbial products. Those do not represent an inflammatory stimulus in steady state conditions but elicit immunosuppressive responses in order to prevent constant detrimental immune activation (Tacke et al., 2009). Intrahepatic macrophages accommodate for both opposing scenarios: promoting immune tolerance during homeostasis as well as implementing proinflammatory mechanisms in acute and chronic liver injury. KCs traditionally denote hepatic (resident) macrophages and represent up to 80–90% of the total body macrophage pool (Ishibashi et al., 2009). Together with LSEC, hepatic stellate cells (HSC), and local immune cells [in particular atypical T-cells, NK-cells (pit cells), and hepatic dendritic cells (DCs)] KCs constitute the non-parenchymal liver cells. They dwell in the lumen of liver sinusoids in close contact to the sinusoidal endothelial cells and sense the circulating blood for food-borne antigens and microbial constituents stemming from the splanchnic circulation. The sinusoidal site also guarantees intimate contact and communication with immune cells that enter the liver via the portal vein. In the non-inflamed liver one of the key functions of KCs is the removal of insoluble macromolecules through phagocytosis mediated by a wide repertoire of pattern-recognition receptors (PRRs) on their surface including scavenger receptors SR-AI and SR-AII, mannose receptor, and Fc-γ receptors (Gao et al., 2008; Figure 1). Thereby, hepatic macrophages eliminate potential harmful threats elicited by degenerated cells, microbes, immune complexes, and toxins (Kolios et al., 2006). KC show functional disparities related to their localization within the liver lobule (Bilzer et al., 2006). Periportal KCs, which are the first macrophages to encounter inflowing portal blood, are more abundant, bigger in size, and exhibit greater phagocytic and lysosomal capacities in addition to an increased production of inflammatory mediators [such as interleukin-1 (IL-1) and tumor necrosis factor (TNF) alpha (TNF-alpha)], in comparison to those hepatic macrophages located in the midzonal area and around the central vein (Sleyster and Knook, 1982; Hoedemakers et al., 1995). Moreover, KCs are not entirely static in the sinusoidal lumen but migrate across the sinusoidal walls and are capable of reducing the sinusoidal blood velocity hence supporting the contact of circulating immune cells with sinusoidal endothelial cells (MacPhee et al., 1992, 1995).

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