The evolving story of macrophages in acute liver failure

State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Medical College, Zhejiang University, Zhejiang, PR China.
Immunology letters (Impact Factor: 2.51). 07/2012; 147(1-2):1-9. DOI: 10.1016/j.imlet.2012.07.002
Source: PubMed


Acute liver failure (ALF) remains a worldwide problem. The innate immune system acts as an important regulator of ALF. Kupffer cells (KCs), the resident macrophages in liver, play a key role in liver innate immune response. Recent researches have shown that macrophages display a remarkable plasticity and can differentiate into functionally diverse subsets. However, the dynamic polarized phenotypes and functional status of macrophages at different stage of ALF are not clear. In this paper, we present a review of evidence that KCs play a significant role in the pathogenesis of ALF, including the phenotype and functions of macrophages, signaling pathways involved in macrophage functional status and cell-crosstalks of KCs with other immune cells. More information on macrophages will promote a better understanding of the cellular molecular mechanisms of ALF and provide new insights for the development of therapeutic targets for ALF.

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    • "Indeed, elevation of hepatic CCL2 following liver damage has previously been demonstrated in alcoholic liver disease [30], non-alcoholic steatohepatitis [31], and in acute liver failure [32]. Furthermore, CCL2 contributes to liver damage and strategies to inhibit CCL2 expression or function appear to be protective in a number of models of liver injury [33,34]. "
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    ABSTRACT: Background Acute liver failure leads to systemic complications with one of the most dangerous being a decline in neurological function, termed hepatic encephalopathy. Neurological dysfunction is exacerbated by an increase of toxic metabolites in the brain that lead to neuroinflammation. Following various liver diseases, hepatic and circulating chemokines, such as chemokine ligand 2 (CCL2), are elevated, though their effects on the brain following acute liver injury and subsequent hepatic encephalopathy are unknown. CCL2 is known to activate microglia in other neuropathies, leading to a proinflammatory response. However, the effects of CCL2 on microglia activation and the pathogenesis of hepatic encephalopathy following acute liver injury remain to be determined. Methods Hepatic encephalopathy was induced in mice via injection of azoxymethane (AOM) in the presence or absence of INCB 3284 dimesylate (INCB), a chemokine receptor 2 inhibitor, or C 021 dihydrochloride (C021), a chemokine receptor 4 inhibitor. Mice were monitored for neurological decline and time to coma (loss of all reflexes) was recorded. Tissue was collected at coma and used for real-time PCR, immunoblots, ELISA, or immunostaining analyses to assess the activation of microglia and consequences on pro-inflammatory cytokine expression. Results Following AOM administration, microglia activation was significantly increased in AOM-treated mice compared to controls. Concentrations of CCL2 in the liver, serum, and cortex were significantly elevated in AOM-treated mice compared to controls. Systemic administration of INCB or C021 reduced liver damage as assessed by serum liver enzyme biochemistry. Administration of INCB or C021 significantly improved the neurological outcomes of AOM-treated mice, reduced microglia activation, reduced phosphorylation of ERK1/2, and alleviated AOM-induced cytokine upregulation. Conclusions These findings suggest that CCL2 is elevated systemically following acute liver injury and that CCL2 is involved in both the microglia activation and neurological decline associated with hepatic encephalopathy. Methods used to modulate CCL2 levels and/or reduce CCR2/CCR4 activity may be potential therapeutic targets for the management of hepatic encephalopathy due to acute liver injury.
    Journal of Neuroinflammation 07/2014; 11(1):121. DOI:10.1186/1742-2094-11-121 · 5.41 Impact Factor
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    • "Knocking out the TNF-α receptor reduces hepatocyte proliferation in APAP toxicity [30], and IL-6 knockout mice are more susceptible to APAP-induced liver injury than the wild type mice [31], suggesting that IL-6 may protect liver from injury. In current study at 48 h, anti-HMGB1 treatment instead of the sham IgG therapy markedly enhanced hepatic TNF-α and IL-6 mRNA levels, the increase in TNF-α and IL-6 at later phase could be due to the fact that macrophages (the classically activated M1 and alternatively activated M2 populations) are proliferating and/or migrating into the liver [32,33], and the M1 subset macrophages might play hepatotoxic role at early stage of ALF, while the M2 subset macrophages likely play hepatoprotective role at late phase of ALF [32]; it is also possible that hepatocytes could also produce these cytokines and their regeneration can be responsible for this increase. The increased TNF-α and IL-6 expression at late phase was associated with better recovered hepatic structure, these results indicate that inflammation might play different roles at different phases in APAP overdose: inflammation likely contributes to liver injury at early phase but also likely improves hepatocyte regeneration and liver recovery at late phase. "
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    ABSTRACT: Acetaminophen (APAP) hepatotoxicity is associated with a high rate of gram-negative enteric bacterial infection; however, the underlying mechanism is still unknown. APAP overdose induces massive hepatocyte necrosis, necrotic tissue releases high mobility group B1 (HMGB1) and exogenous HMGB1 is able to induce gut bacterial translocation (BT) in normal mice; therefore, it is possible that HMGB1 mediates gut BT in APAP hepatotoxicity. This study aims to test this hypothesis by using anti-HMGB1 neutralizing antibody to treat APAP overdose for 24-48 hours. Male C57BL/6 mice were intraperitoneally (i.p.) injected with a single dose of APAP (350 mg/kg dissolved in 1mL sterile saline). 2 hrs after APAP injection, the APAP challenged mice were randomized to receive treatment with either anti-HMGB1 antibody (400 mug per dose) or non-immune (sham) IgG every 24 h for a total of 2 doses. 24 and 48 hrs after APAP challenge, anti-HMGB1 treatment instead of sham IgG therapy significantly decreased serum HMGB1 concentrations and reduced BT by 85%; serum HMGB1 levels were positively correlated with the amount of BT; anti-HMGB1 therapy decreased hepatic BT at 48 h, which was associated with better recovered liver structure and better restored hepatic immune system that was shown by enhanced hepatic mRNA expression of TNF-alpha, IL-6 and extensive proliferation of inflammatory and reticuloendothelial cells; however, anti-HMGB1 treatment did not decrease gut mucosal permeability as compared to the sham IgG therapy at either 24 or 48 hrs. HMGB1 neutralization is associated with bacterial translocation during APAP hepatotoxicity.
    BMC Gastroenterology 04/2014; 14(1):66. DOI:10.1186/1471-230X-14-66 · 2.37 Impact Factor
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    ABSTRACT: Inflammation and infection have long been known to affect the activity and expression of enzymes involved in hepatic and extrahepatic drug clearance. Significant advances have been made to elucidate the molecular mechanisms underlying the complex cross-talk between inflammation and drug-metabolism alterations. The emergent role of ligand-activated transcriptional regulators, belonging to the nuclear receptor (NR) superfamily, is now well established. The NRs, pregnane X receptor, constitutive androstane receptor, retinoic X receptor, glucocorticoid receptor, and hepatocyte nuclear factor 4, and the basic helix-loop-helix/Per-ARNT-Sim family member, aryl hydrocarbon receptor, are the main regulators of the detoxification function. According to the panel of mediators secreted during inflammation, a cascade of numerous signaling pathways is activated, including nuclear factor kappa B, mitogen-activated protein kinase, and the Janus kinase/signal transducer and activator of transcription pathways. Complex cross-talk is established between these signaling pathways regulating either constitutive or induced gene expression. In most cases, a mutual antagonism between xenosensor and inflammation signaling occurs. This review focuses on the molecular and cellular mechanisms implicated in this cross-talk.
    Drug Metabolism Reviews 02/2013; 45(1):122-144. DOI:10.3109/03602532.2012.756011 · 5.36 Impact Factor
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