Increased Killing of Liver NK Cells by Fas/Fas Ligand and NKG2D/NKG2D Ligand Contributes to Hepatocyte Necrosis in Virus-Induced Liver Failure

Zou, Yong; Chen, Tao; Han, Meifang; Wang, Hongwu; Yan, Weiming; Song, Ge; Wu, Zhourui; Wang, Xiaojing; Zhu, Chuanlong; Luo, Xiaoping; Ning, Qin

doi:10.4049/jimmunol.0900687

Cited by 118 publications

(118 citation statements)

References 36 publications

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“…Previous studies have focused on the first "beat," and they suggest that natural killer (NK) cells (29), Kupffer cells (30), dendritic cells (DCs) (24), monocytes, Th1 cells (30), Th17 cells (23,31), regulatory T (Treg) cells (21), and other immunologically relevant cells are all involved in the pathogenesis of liver injury in ACLF. The increased Treg cells, monocytes, and other cells lead to elevated TGF-␤1 expression.…”

Section: Discussionmentioning

confidence: 99%

The Transforming Growth Factor β1/Interleukin-31 Pathway Is Upregulated in Patients with Hepatitis B Virus-Related Acute-on-Chronic Liver Failure and Is Associated with Disease Severity and Survival

Guo

Ming

et al. 2015

Clin. Vaccine Immunol.

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The transforming growth factor ␤1/interleukin-31 (TGF-␤1/IL-31) pathway plays an important role in the process of cell injury and inflammation. The purpose of this work was to explore the role of the TGF-␤1/IL-31 pathway in the cytopathic process of hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF). The quantitative serum levels of TGF-␤1, IL-9, IL-10, IL-17, IL-22, IL-23, IL-31, IL-33, and IL-35 were analyzed among chronic hepatitis B (CHB) patients (n ‫؍‬ 17), ACLF patients (n ‫؍‬ 18), and normal control (NC) subjects (n ‫؍‬ 18). Disease severity in patients with ACLF was assessed using the model for endstage liver disease (MELD) and Child-Pugh scores. Serum TGF-␤1 levels were strongly positively correlated with IL-31 in all subjects, and both of them were positively correlated with IL-17, IL-22, and IL-33. In CHB and ACLF patients, serum levels of TGF-␤1 and IL-31 were both increased significantly compared with those in NC subjects and positively correlated with total bilirubin (TBil) and alpha-fetoprotein (AFP) levels. ACLF patients showed the highest levels of TGF-␤1 and IL-31, which were positively correlated with Child-Pugh scores. Furthermore, the recovery from the liver injury in CHB was accompanied by decreased TGF-␤1 and IL-31 levels. More importantly, serum levels of TGF-␤1 and IL-31 were markedly upregulated in ACLF nonsurvivors, and IL-31 displayed the highest sensitivity and specificity (85.7% and 100.0%, respectively) in predicting nonsurvival of ACLF patients. Increasing activity of the TGF-␤1/IL-31 pathway is well correlated with the extent of liver injury, disease severity, and nonsurvival of ACLF patients, while reducing activity is detected along the recovery from liver injury in CHB, suggesting its potential role in the pathogenesis of liver injury during chronic HBV infection. Hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF) is triggered mainly by severe extensive liver injury, and the exact mechanisms of massive destruction of HBV-infected hepatocytes remain unclear. However, one of the current assumptions is that the imbalance of the cytokine network, the so-called cytokine storm theory (1), points to potential involvement of inflammatory cytokines in destroying the HBV-infected cells, which may provide an explanation for the aggravation of liver injury.Transforming growth factor-␤1 (TGF-␤1) is a 25-kDa homodimeric protein composed of two subunits linked by a disulfide bond and is a powerful inhibitor of DNA synthesis and cellular proliferation (2). It also mediates formation of extracellular matrix and facilitates cell differentiation (3). Previous studies have shown that TGF-␤1 plays a role in developing liver failure (LF). Miwa et al. found that the mRNA and protein expression of TGF-␤1 were significantly upregulated in both the plasma and liver tissue in patients with fulminant liver failure (FLF) (4). Yoshimoto et al. found that the overexpression of TGF-␤1 delayed liver regeneration and promoted perisinusoidal fibrosis and hepatocyte apoptos...

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Section: Discussionmentioning

confidence: 99%

The Transforming Growth Factor β1/Interleukin-31 Pathway Is Upregulated in Patients with Hepatitis B Virus-Related Acute-on-Chronic Liver Failure and Is Associated with Disease Severity and Survival

Guo

Ming

et al. 2015

Clin. Vaccine Immunol.

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“…4). As a comparable example, liver NK cells were implicated in the emergence of fulminant hepatic failure following mouse hepatitis virus infection, whereas the depletion of NK cells limited liver damage and increased animal survival (90). Alternatively, IFN-g was also associated with both neuronal protection and repair by modulation of microglia properties (91), so we can propose that NK cells secreting IFN-g following infection may have a neuroprotective function (Fig.…”

Section: Nk Cell Modifications Associated With Cns Disordersmentioning

confidence: 95%

NK Cells in Central Nervous System Disorders

Poli

Kmiecik

Domingues

et al. 2013

The Journal of Immunology

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NK cells are important players in immunity against pathogens and neoplasms. As a component of the innate immune system, they are one of the first effectors on sites of inflammation. Through their cytokine production capacities, NK cells participate in the development of a potent adaptive immune response. Furthermore, NK cells were found to have regulatory functions to limit and prevent autoimmunity via killing of autologous immune cells. These paradoxical functions of NK cells are reflected in CNS disorders. In this review, we discuss the phenotypes and functional features of peripheral and brain NK cells in brain tumors and infections, neurodegenerative diseases, acute vascular and traumatic damage, as well as mental disorders. We also discuss the implication of NK cells in neurotoxicity and neuroprotection following CNS pathology, as well as the crosstalk between NK cells and brain-resident immune cells.

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“…Nevertheless, this seems of great clinical importance as NK and NKT cells have been reproducibly shown to be functionally relevant in acute liver disease models. [18][19][20] Therefore, we here analyze the specific role of CXCR3 and its impact on NK and NKT cell recruitment during the early phases of toxic liver damage.…”

Section: Cxcr3 In Acute Toxic Liver Injurymentioning

confidence: 99%

The chemokine receptor CXCR3 limits injury after acute toxic liver damage

Zaldivar

Berres

Sahin

et al. 2012

Laboratory Investigation

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Although acute liver failure is a rare disease, its presence is associated with high morbidity and mortality in affected patients. While a contribution of the immune system to the outcome of toxic liver failure is anticipated, functionally relevant immune cell receptors for liver cell damage need to be better defined. We here investigate the relevance of the chemokine receptor CXCR3, which is important for hepatic immune cell infiltration, in a model of experimental acute liver failure. Liver injury was induced by a single intraperitoneal injection of carbon tetrachloride (CCl 4 ) in CXCR3 À/À , CCR1 À/À , CCR5 À/À and wild-type mice. In this model, CXCR3 À/À mice displayed augmented liver damage compared with all other mouse strains as assessed by liver histology and serum transaminases 24 and 72 h after injury. Phenotypically, CXCR3 À/À mice had significantly reduced intrahepatic NK and NKT cells after injury at all investigated time points (all Po0.05), but strongly elevated expression levels of IL1-b, TNF-a and IFN-g. In line with a functional role of innate immune cells, wildtype mice depleted for NK cells with an anti-ASIALO GM1 antibody before liver injury also displayed increased liver injury after CCl 4 challenge. CXCR3 À/À and NK cell-depleted mice show reduced apoptotic liver cells (TUNEL assay), but more necrotic hepatocytes. Functionally, the augmented liver cell necrosis in CXCR3 À/À and NK cell-depleted mice was associated with increased expression of high mobility group 1 (HMGB1) protein and a consecutive enhanced infiltration of neutrophils into the liver. In conclusion, the results demonstrate a primarily unexpected beneficial role of CXCR3 in acute toxic liver injury. These findings should be taken into account when planning trials with CXCR3 antagonists. Although liver failure is a quite rare clinical condition, its appearance is associated with high mortality and morbidity in affected individuals. The main identifiable causes of acute liver failure are drugs, toxins and viral infections. 1 From a pathophysiological point of view, acute toxic liver failure results from a massive necrosis of hepatocytes that provokes a strong inflammatory immune response within the liver. 2 Upon activation, liver resident and infiltrating immune cells (including T cells, NK cells and NKT cells) secrete diverse proinflammatory chemokines and cytokines, including interferon (IFN)-g 3,4 which perpetuate liver cell damage. IFN-g in turn strongly activates the transcription of the chemokines CXCL9, CXCL10 and CXCL11. 5 The canonical receptor for all three chemokines is CXCR3, 6 which is expressed on various cell sub-populations within the liver, including liver endothelial cells, stellate cells, T cells, NK cells 7 and NKT cells. 8 The interaction between these three chemokines and their receptor mediates the attachment of these immune cells to endothelial cells 9 and thus appears to be crucial for the recruitment of T, NK and NKT cells into the liver. 10,11 Activated hepatic NKT cells by themselves also secrete la...

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Increased Killing of Liver NK Cells by Fas/Fas Ligand and NKG2D/NKG2D Ligand Contributes to Hepatocyte Necrosis in Virus-Induced Liver Failure

Cited by 118 publications

References 36 publications

The Transforming Growth Factor β1/Interleukin-31 Pathway Is Upregulated in Patients with Hepatitis B Virus-Related Acute-on-Chronic Liver Failure and Is Associated with Disease Severity and Survival

The Transforming Growth Factor β1/Interleukin-31 Pathway Is Upregulated in Patients with Hepatitis B Virus-Related Acute-on-Chronic Liver Failure and Is Associated with Disease Severity and Survival

NK Cells in Central Nervous System Disorders

The chemokine receptor CXCR3 limits injury after acute toxic liver damage

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