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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) contribution to acute liver injury. Acute hepatocyte damage in response to multitude events leads to release of various DAMPs including HSPs and HMGB-1, which bind to TLR4 on KCs, and other cell contents (RNA, DNA) binding to various TLRs. TLR4 engagement activates NF-κB pathways in KC resulting in the synthesis of a myriad of proinflammatory cytokines, chemokines, reactive oxygen, and nitrogen species. KC-secreted TNF-alpha is central in the augmentation of liver injury mainly by inducing hepatocyte apoptosis, but also by deterioration of hepatic microcirculation through swelling and activation of endothelial cells with subsequent sinusoidal platelet aggregation and facilitation of peripheral immune cells entry. Activated KCs secrete IL-1beta and CXC chemokines such as CXCL2 and CXCL8 (IL-8), whereby neutrophils are massively attracted and start releasing ROS and proteases evoking hepatocyte necrosis. In addition, KCs, injured hepatocytes and activated hepatic stellate cells secrete CCL2 and other CC chemokines mediating liver influx of bone-marrow-derived monocytes that expand the local macrophage pool. Hepatic macrophages are also stimulated by IFN-gamma from resident and recruited T-cells and NK-cells and by C5a. KCs actively govern NK cell activation and recruitment by the production of IL-12/IL-18 which in turn induces hepatocyte death via membrane-bound FasL. High levels of LPS arising from Gram-negative bacteria in the context of increased bacterial translocation during acute liver injury magnify the activation the liver macrophages. As a counter-regulatory effect, hepatic macrophages also secrete IL-4, IL-6, and IL-10 amongst others that may dampen hepatic injury by either direct or indirect mechanisms. Engulfment of cell debris may either contain or amplify tissue injury (not depicted here). The blue box in the right lower corner illustrates important proapoptotic and prosurvival pathways in hepatocytes after binding of KC-related effector molecules during acute liver injury. TNF-alpha elicits both apoptosis (mainly via TNF-R1 and subsequent downstream signaling involving TRADD, FADD, and effector caspases) and cell survival through activation of NF-κB downstream cascade. Soluble and membrane-bound FasL derived from activated KCs and NK-cells also leads to caspase-dependent cell death after direct engagement of FADD. IL-6 complexes with gp80 and gp130 resulting in STAT3 activation via Janus kinases (JAKs) that can promote cell protection. Abbreviations: C5a, complement factor 5a; FADD, Fas-associated death domain; HMGB-1, high mobility group box-1; HSP, heat-shock protein; IL, interleukin; NF-κB, nuclear-factor-kappaB; ROS, reactive oxygen species; STAT3, signal transducer and activator of transcription 3; TNFa, tumor necrosis factor alpha; TRADD, TNF receptor associated death domain.
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Figure 2: Kupffer cell (KC)/Macrophage (MΦ) contribution to acute liver injury. Acute hepatocyte damage in response to multitude events leads to release of various DAMPs including HSPs and HMGB-1, which bind to TLR4 on KCs, and other cell contents (RNA, DNA) binding to various TLRs. TLR4 engagement activates NF-κB pathways in KC resulting in the synthesis of a myriad of proinflammatory cytokines, chemokines, reactive oxygen, and nitrogen species. KC-secreted TNF-alpha is central in the augmentation of liver injury mainly by inducing hepatocyte apoptosis, but also by deterioration of hepatic microcirculation through swelling and activation of endothelial cells with subsequent sinusoidal platelet aggregation and facilitation of peripheral immune cells entry. Activated KCs secrete IL-1beta and CXC chemokines such as CXCL2 and CXCL8 (IL-8), whereby neutrophils are massively attracted and start releasing ROS and proteases evoking hepatocyte necrosis. In addition, KCs, injured hepatocytes and activated hepatic stellate cells secrete CCL2 and other CC chemokines mediating liver influx of bone-marrow-derived monocytes that expand the local macrophage pool. Hepatic macrophages are also stimulated by IFN-gamma from resident and recruited T-cells and NK-cells and by C5a. KCs actively govern NK cell activation and recruitment by the production of IL-12/IL-18 which in turn induces hepatocyte death via membrane-bound FasL. High levels of LPS arising from Gram-negative bacteria in the context of increased bacterial translocation during acute liver injury magnify the activation the liver macrophages. As a counter-regulatory effect, hepatic macrophages also secrete IL-4, IL-6, and IL-10 amongst others that may dampen hepatic injury by either direct or indirect mechanisms. Engulfment of cell debris may either contain or amplify tissue injury (not depicted here). The blue box in the right lower corner illustrates important proapoptotic and prosurvival pathways in hepatocytes after binding of KC-related effector molecules during acute liver injury. TNF-alpha elicits both apoptosis (mainly via TNF-R1 and subsequent downstream signaling involving TRADD, FADD, and effector caspases) and cell survival through activation of NF-κB downstream cascade. Soluble and membrane-bound FasL derived from activated KCs and NK-cells also leads to caspase-dependent cell death after direct engagement of FADD. IL-6 complexes with gp80 and gp130 resulting in STAT3 activation via Janus kinases (JAKs) that can promote cell protection. Abbreviations: C5a, complement factor 5a; FADD, Fas-associated death domain; HMGB-1, high mobility group box-1; HSP, heat-shock protein; IL, interleukin; NF-κB, nuclear-factor-kappaB; ROS, reactive oxygen species; STAT3, signal transducer and activator of transcription 3; TNFa, tumor necrosis factor alpha; TRADD, TNF receptor associated death domain.

Mentions: In absence of liver inflammation, the number of intrahepatic macrophages is maintained at constant numbers. Various cytokines comprising IL-1, IL-4, interferon-gamma (IFN-gamma), granulocyte–macrophage colony-stimulating factor (GM-CSF), and other hematopoietic factors promote macrophage apoptosis and survival in vitro (Naito et al., 2004). Results of studies covering the life span of KCs are inconsistent and range between 14 days and several months (Naito et al., 2004). Interestingly, even in monocytopenic species KC persistence in situ may exceed 6 weeks, suggesting that KCs constitute long-lived resident macrophages (Naito et al., 2004). Nevertheless, constant turnover is present and hepatic macrophages are incessantly repopulated. Previous concepts of resident macrophages deriving from precursor cells (Yamamoto et al., 1996; Naito et al., 1997; Duffield et al., 2005) have been refuted by more recent studies that indicate that a significant extent of repopulation of these cells is from bone-marrow-derived myeloid precursors (Klein et al., 2007). In line, in one study only 1.5% of hepatic macrophages incorporated 3H-thymidine during steady state, indicative of a low proliferation index (Crofton et al., 1978). In acute and chronic liver injury the intrahepatic macrophage count is massively expanded following the influx of peripheral monocytes (Figure 2) rather than augmentation of tissue-resident macrophages (Duffield et al., 2005; Imamura et al., 2005; Holt et al., 2008; Karlmark et al., 2009; Zimmermann et al., 2010). However, a current paper indicating that IL-4 dependent rapid in situ proliferation of local macrophages in Th2-biased inflammation accounts for extension of tissue alternatively activated macrophages (AAM), has challenged our prevailing understanding of a predominant monocytic contribution to augmented hepatic macrophage pool and sparked intensive debate (Jenkins et al., 2011; Tacke and Kurts, 2011). Indeed, under certain circumstances the intrahepatic macrophage infiltrate might actually be preferentially polarized towards the M2 phenotype (synonymous for AAM) as it has been observed in acetaminophen (APAP) treated mice by Holt et al. (2008). Congruently, these cells elicited a protective role by promoting inflammation resolution and tissue repair. Yet, as far as other experimental models of ALI are concerned, it is tempting to speculate that macrophage actions in these conditions are rather dominated by classically activated M1 macrophages (CAM) emanating from infiltrating monocytes. This hypothesis is supported by observations in acute carbon tetrachloride (CCl4) mediated liver injury in mice. Upon injury, the fraction of Ly6chi CD11b+ F4/80+ monocytes, representing the peripheral inflammatory monocyte subset, is significantly enlarged, whereas Ly6clo CD11b+ F4/80− or Ly6clo CD11b− F4/80++ cells, corresponding to either unconventional or resident macrophages, remain stable (Karlmark et al., 2009). Thus, the major body of evidence indicates that a large proportion of intrahepatic macrophages directly derives from blood-borne monocytes in conditions of experimental ALI. However, a thorough inspection of the nature of infiltrating macrophages is warranted, and it is likely that the paramount macrophage phenotype strongly depends on the respective injury model.


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) contribution to acute liver injury. Acute hepatocyte damage in response to multitude events leads to release of various DAMPs including HSPs and HMGB-1, which bind to TLR4 on KCs, and other cell contents (RNA, DNA) binding to various TLRs. TLR4 engagement activates NF-κB pathways in KC resulting in the synthesis of a myriad of proinflammatory cytokines, chemokines, reactive oxygen, and nitrogen species. KC-secreted TNF-alpha is central in the augmentation of liver injury mainly by inducing hepatocyte apoptosis, but also by deterioration of hepatic microcirculation through swelling and activation of endothelial cells with subsequent sinusoidal platelet aggregation and facilitation of peripheral immune cells entry. Activated KCs secrete IL-1beta and CXC chemokines such as CXCL2 and CXCL8 (IL-8), whereby neutrophils are massively attracted and start releasing ROS and proteases evoking hepatocyte necrosis. In addition, KCs, injured hepatocytes and activated hepatic stellate cells secrete CCL2 and other CC chemokines mediating liver influx of bone-marrow-derived monocytes that expand the local macrophage pool. Hepatic macrophages are also stimulated by IFN-gamma from resident and recruited T-cells and NK-cells and by C5a. KCs actively govern NK cell activation and recruitment by the production of IL-12/IL-18 which in turn induces hepatocyte death via membrane-bound FasL. High levels of LPS arising from Gram-negative bacteria in the context of increased bacterial translocation during acute liver injury magnify the activation the liver macrophages. As a counter-regulatory effect, hepatic macrophages also secrete IL-4, IL-6, and IL-10 amongst others that may dampen hepatic injury by either direct or indirect mechanisms. Engulfment of cell debris may either contain or amplify tissue injury (not depicted here). The blue box in the right lower corner illustrates important proapoptotic and prosurvival pathways in hepatocytes after binding of KC-related effector molecules during acute liver injury. TNF-alpha elicits both apoptosis (mainly via TNF-R1 and subsequent downstream signaling involving TRADD, FADD, and effector caspases) and cell survival through activation of NF-κB downstream cascade. Soluble and membrane-bound FasL derived from activated KCs and NK-cells also leads to caspase-dependent cell death after direct engagement of FADD. IL-6 complexes with gp80 and gp130 resulting in STAT3 activation via Janus kinases (JAKs) that can promote cell protection. Abbreviations: C5a, complement factor 5a; FADD, Fas-associated death domain; HMGB-1, high mobility group box-1; HSP, heat-shock protein; IL, interleukin; NF-κB, nuclear-factor-kappaB; ROS, reactive oxygen species; STAT3, signal transducer and activator of transcription 3; TNFa, tumor necrosis factor alpha; TRADD, TNF receptor associated death domain.
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Figure 2: Kupffer cell (KC)/Macrophage (MΦ) contribution to acute liver injury. Acute hepatocyte damage in response to multitude events leads to release of various DAMPs including HSPs and HMGB-1, which bind to TLR4 on KCs, and other cell contents (RNA, DNA) binding to various TLRs. TLR4 engagement activates NF-κB pathways in KC resulting in the synthesis of a myriad of proinflammatory cytokines, chemokines, reactive oxygen, and nitrogen species. KC-secreted TNF-alpha is central in the augmentation of liver injury mainly by inducing hepatocyte apoptosis, but also by deterioration of hepatic microcirculation through swelling and activation of endothelial cells with subsequent sinusoidal platelet aggregation and facilitation of peripheral immune cells entry. Activated KCs secrete IL-1beta and CXC chemokines such as CXCL2 and CXCL8 (IL-8), whereby neutrophils are massively attracted and start releasing ROS and proteases evoking hepatocyte necrosis. In addition, KCs, injured hepatocytes and activated hepatic stellate cells secrete CCL2 and other CC chemokines mediating liver influx of bone-marrow-derived monocytes that expand the local macrophage pool. Hepatic macrophages are also stimulated by IFN-gamma from resident and recruited T-cells and NK-cells and by C5a. KCs actively govern NK cell activation and recruitment by the production of IL-12/IL-18 which in turn induces hepatocyte death via membrane-bound FasL. High levels of LPS arising from Gram-negative bacteria in the context of increased bacterial translocation during acute liver injury magnify the activation the liver macrophages. As a counter-regulatory effect, hepatic macrophages also secrete IL-4, IL-6, and IL-10 amongst others that may dampen hepatic injury by either direct or indirect mechanisms. Engulfment of cell debris may either contain or amplify tissue injury (not depicted here). The blue box in the right lower corner illustrates important proapoptotic and prosurvival pathways in hepatocytes after binding of KC-related effector molecules during acute liver injury. TNF-alpha elicits both apoptosis (mainly via TNF-R1 and subsequent downstream signaling involving TRADD, FADD, and effector caspases) and cell survival through activation of NF-κB downstream cascade. Soluble and membrane-bound FasL derived from activated KCs and NK-cells also leads to caspase-dependent cell death after direct engagement of FADD. IL-6 complexes with gp80 and gp130 resulting in STAT3 activation via Janus kinases (JAKs) that can promote cell protection. Abbreviations: C5a, complement factor 5a; FADD, Fas-associated death domain; HMGB-1, high mobility group box-1; HSP, heat-shock protein; IL, interleukin; NF-κB, nuclear-factor-kappaB; ROS, reactive oxygen species; STAT3, signal transducer and activator of transcription 3; TNFa, tumor necrosis factor alpha; TRADD, TNF receptor associated death domain.
Mentions: In absence of liver inflammation, the number of intrahepatic macrophages is maintained at constant numbers. Various cytokines comprising IL-1, IL-4, interferon-gamma (IFN-gamma), granulocyte–macrophage colony-stimulating factor (GM-CSF), and other hematopoietic factors promote macrophage apoptosis and survival in vitro (Naito et al., 2004). Results of studies covering the life span of KCs are inconsistent and range between 14 days and several months (Naito et al., 2004). Interestingly, even in monocytopenic species KC persistence in situ may exceed 6 weeks, suggesting that KCs constitute long-lived resident macrophages (Naito et al., 2004). Nevertheless, constant turnover is present and hepatic macrophages are incessantly repopulated. Previous concepts of resident macrophages deriving from precursor cells (Yamamoto et al., 1996; Naito et al., 1997; Duffield et al., 2005) have been refuted by more recent studies that indicate that a significant extent of repopulation of these cells is from bone-marrow-derived myeloid precursors (Klein et al., 2007). In line, in one study only 1.5% of hepatic macrophages incorporated 3H-thymidine during steady state, indicative of a low proliferation index (Crofton et al., 1978). In acute and chronic liver injury the intrahepatic macrophage count is massively expanded following the influx of peripheral monocytes (Figure 2) rather than augmentation of tissue-resident macrophages (Duffield et al., 2005; Imamura et al., 2005; Holt et al., 2008; Karlmark et al., 2009; Zimmermann et al., 2010). However, a current paper indicating that IL-4 dependent rapid in situ proliferation of local macrophages in Th2-biased inflammation accounts for extension of tissue alternatively activated macrophages (AAM), has challenged our prevailing understanding of a predominant monocytic contribution to augmented hepatic macrophage pool and sparked intensive debate (Jenkins et al., 2011; Tacke and Kurts, 2011). Indeed, under certain circumstances the intrahepatic macrophage infiltrate might actually be preferentially polarized towards the M2 phenotype (synonymous for AAM) as it has been observed in acetaminophen (APAP) treated mice by Holt et al. (2008). Congruently, these cells elicited a protective role by promoting inflammation resolution and tissue repair. Yet, as far as other experimental models of ALI are concerned, it is tempting to speculate that macrophage actions in these conditions are rather dominated by classically activated M1 macrophages (CAM) emanating from infiltrating monocytes. This hypothesis is supported by observations in acute carbon tetrachloride (CCl4) mediated liver injury in mice. Upon injury, the fraction of Ly6chi CD11b+ F4/80+ monocytes, representing the peripheral inflammatory monocyte subset, is significantly enlarged, whereas Ly6clo CD11b+ F4/80− or Ly6clo CD11b− F4/80++ cells, corresponding to either unconventional or resident macrophages, remain stable (Karlmark et al., 2009). Thus, the major body of evidence indicates that a large proportion of intrahepatic macrophages directly derives from blood-borne monocytes in conditions of experimental ALI. However, a thorough inspection of the nature of infiltrating macrophages is warranted, and it is likely that the paramount macrophage phenotype strongly depends on the respective injury model.

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