Liver NK cells expressing TRAIL are toxic against self hepatocytes in mice

Ochi, Makoto; Ohdan, Hideki; Mitsuta, Hiroshi; Onoe, Takashi; Tokita, Daisuke; Hara, Hidetaka; Ishiyama, K.; Zhou, Wendy; Tanaka, Yuka; Asahara, Toshimasa

doi:10.1002/hep.20204

Cited by 124 publications

(123 citation statements)

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“…These cells are known to be involved in liver injury 33 where they mediate apoptosis of different liver resident cells. 34,35 However, their specific role in acute CCl 4 -mediated liver injury has not yet been elucidated. As NK cells might also be responsible for the increased liver damage in CXCR3 À/À mice, we depleted these cells with an anti-mouse ASIALO GM1 antibody in wild-type mice before liver injury.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

“…As NK cells have been associated with apoptotic cell injury, 34 a TUNEL assay was performed on cryosections of the livers from CXCR3 À/À and wild-type mice. As depicted in Figure 5a, CXCR3 À/À mice indeed had fewer apoptotic liver cells 24 and 72 h after CCl 4 administration compared with wild-type mice.…”

Section: Discussionmentioning

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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“…Activated hepatic NK cells are able to kill hepatocytes and induce liver injury such as viral liver infection (adenovirus), Pseudomonas aeruginosa exotoxin A (PEA) injection and carrageenan administration [9][10][11], and polyinosinic:polycytidylic acid [Poly(I:C)] injection as reported by Makoto Ochi et al and us [12,13]. Mole-cules including IFN-c, IL-12, Perforin and TRAIL contributed to NK cell cytotoxicity against hepatocytes [9,[11][12][13]. Furthermore, pre-activated T cells by a low dose of ConA could enhance the ability of Poly(I:C)-activated NK cells to cause more severe hepatocyte injury [14].…”

Section: Introductionmentioning

confidence: 91%

Liver-specific HBsAg transgenic mice are over-sensitive to Poly(I:C)-induced liver injury in NK cell- and IFN-γ-dependent manner

Chen

Sun

Jiang

et al. 2007

Journal of Hepatology

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Background/Aims: The role of natural killer (NK) cells in the development of hepatitis B virus (HBV)-associated liver injury remains obscure. In this study, we elucidated the role of NK cells in liver injury of HBsAg transgenic mice (HBs-B6), a mimic of human healthy chronic HBsAg carriers, triggered by polyinosinic:polycytidylic acid [Poly(I:C)].Methods: HBs-B6 or wild B6 mice were intraperitoneally injected with Poly(I:C) at different doses. Liver injury was evaluated by serum transaminase activity and histopathologic changes.Results: HBs-B6 mice were over-sensitive to Poly(I:C)-induced liver injury, which was absolutely dependent on the presence of NK cells and IFN-c produced by intrahepatic NK cells. Much stronger IFN-c receptor expression was observed on hepatocytes of HBs-B6 mice, which was significantly enhanced by Poly(I:C) injection. Treatment with IFN-c in vitro triggered much higher activation of downstream signals (pSTAT1-IRF-1) in hepatocytes of HBs-B6 mice. Depletion of Kupffer cells and neutralization of endogenous IL-12 did not affect Poly(I:C)-induced over-sensitive liver injury in HBs-B6 mice.Conclusions: NK cells played a critical role in an IFN-c dependent, Kupffer cell-and IL-12-independent manner in oversensitive liver injury triggered by Poly(I:C) in murine chronic HBsAg carriers. Ó

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“…20 Importantly, NK cells are quite abundant in the liver of mice, in contrast to a relatively small percentage in the peripheral lymphatics, and they mediate higher cytotoxic activity against tumor cells than spleen or peripheral NK cells in rodents. 21 The underlying reason may be that TRAIL expression is highly inducible by interleukin-2 (IL-2) in liver NK cells, whereas this effect has been barely observed in peripheral NK cells. 22 This finding has recently been used in a preclinical approach to enhance the efficacy of liver transplantation, for which recurrent hepatocellular carcinoma (HCC) is one of the most fatal complications.…”

Section: Therapeutic Intervention In Liver Disease With Trail As a Pomentioning

confidence: 99%

On the TRAIL to therapeutic intervention in liver disease

2007

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Hepatocellular carcinoma (HCC) ranks among the 10 most common cancers worldwide. The fact that HCC is resistant to conventional chemotherapy and is rarely amenable to radiotherapy leaves this disease with no effective therapeutic options and a very poor prognosis. Therefore, the development of more effective therapeutic tools and strategies is much needed. HCCs are phenotypically and genetically heterogeneous tumors that commonly emerge on a background of chronic liver diseases, most of which culminate in cirrhosis, such as alcoholic cirrhosis and chronic hepatitis B and C infections. This review outlines recent findings on the progression of liver disease, including our knowledge of the role of apoptotic processes, with an emphasis on the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). The proapoptotic and antiapoptotic properties of TRAIL, its involvement in liver injury, and its potential as a therapeutic agent in fibrosis and HCC are discussed. Several contradictory and confusing data have not yet been resolved or placed into perspective, such as the influence of factors that determine the TRAIL sensitivity of target cells, including the tumor microenvironment or cirrhotic tissue. Therefore, we assess these data from the perspectives of gastroenterologists (P.S. and M.W.B.) and a molecular oncologist (I.H.) with research interests in liver injury, apoptosis, and experimental therapeutics. (HEPATOLOGY

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Liver NK cells expressing TRAIL are toxic against self hepatocytes in mice

Cited by 124 publications

References 50 publications

The chemokine receptor CXCR3 limits injury after acute toxic liver damage

The chemokine receptor CXCR3 limits injury after acute toxic liver damage

Liver-specific HBsAg transgenic mice are over-sensitive to Poly(I:C)-induced liver injury in NK cell- and IFN-γ-dependent manner

On the TRAIL to therapeutic intervention in liver disease

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