Enhanced T cell transmigration across the murine liver sinusoidal endothelium is mediated by transcytosis and surface presentation of chemokines†

Schrage, Arnhild; Wechsung, Katja; Neumann, Katrin; Schümann, Michael; Schulzke, Jörg–Dieter; Engelhardt, Britta; Zeitz, Martin; Hamann, Alf; Klugewitz, Katja

doi:10.1002/hep.22443

Cited by 61 publications

(56 citation statements)

References 45 publications

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“…16,20 Notably, in this model, we have already noted a strong induction of the CXCR3 ligand CXCL9 within the liver, 17 which was identified as a CXCR3 in acute toxic liver injury MM Zaldivar et al major chemokine for hepatic recruitment of NK and NKT cells 11 by mediating their transendothelial migration. 30 As we observed that CXCR3 À/À mice were more prone to severe liver damage in the CCl 4 model, we thus assessed whether this phenotype is associated with an altered recruitment of T, NK and NKT cells into the liver. Indeed, a dominant immune phenotype of the CXCR3 À/À mice used in our study was the reduced NK and NKT cell recruitment after the toxic insult (Figure 2), together with a reduced mRNA expression of perforin, a major cytolytic protein of these cells (Figure 3).…”

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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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%

The chemokine receptor CXCR3 limits injury after acute toxic liver damage

Zaldivar

Berres

Sahin

et al. 2012

Laboratory Investigation

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“…The chemoattractant function of resident liver cells such as hepatocytes or LSECs has already been identified [49,50] . Recently, it has been demonstrated that CCR5-binding chemokines CCL3, CCL4 and CCL5 were expressed in the liver upon ConA challenge.…”

Section: The Role Of Chemokines and Chemokine Receptors In Cona Hepatmentioning

confidence: 99%

Tolerance Induction in Response to Liver Inflammation

Erhardt

Tiegs

2010

Dig Dis

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Background/Aims: The liver plays an important role in immunological tolerance due to its anatomical location, as it links the gastrointestinal tract and the systemic venous circulation. Therefore, immune reactions against dietary or bacterial antigens from the gut have to be avoided. However, immune responses resulting in elimination of harmful hepatotrophic pathogens have to be induced. We investigated mechanisms of tolerance induction in response to liver inflammation in a murine model of immune-mediated liver injury. Methods: Liver damage was induced by injection of the plant lectin concanavalin A (ConA). Cytokine levels were measured in plasma and liver tissue. The frequencies of intrahepatic and splenic cell subsets were measured by FACS analyses. Results: ConA hepatitis was mediated by activation of CD4+ T cells, NKT cells and Kupffer cells releasing IFN-γ and TNF-α. Tolerance developed towards ConA rechallenge within 8 days, lasted for several weeks and was characterized by significantly reduced plasma transaminase activities, decreased Th1/Th17 responses and an increased IL-10 release, the latter being produced by CD4+CD25+FoxP3+ regulatory T cells and Kupffer cells. Moreover, regulatory T cells from ConA-tolerant mice displayed a higher immunosuppressive potential in vitro and in vivo compared to those from non-tolerant animals. Interestingly, ConA hepatitis was aggravated in CCR5^–/– and CXCR3^–/– mice. Conclusion: These results suggest that ConA tolerance is mediated by induced IL10+ regulatory T cells, probably trafficking into the liver depending on the IFN-γ-inducible chemokine receptors CCR5 and CXCR3.

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“…These are produced by macrophages, i.e., the Kupffer cells in the liver and are also implicated in the recruitment of Th1 cells via the same receptor CXCR3. Alternatively the sinusoidal endothelial cells may be another site of their production [129,130] . MIG and IP-10 are also secreted by biliary epithelial cells and activated stellate cells [131,132] .…”

Section: Chemokines In Pbcmentioning

confidence: 99%

Primary biliary cirrhosis: From bench to bedside

Notas

2015

WJGPT

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Primary biliary cirrhosis (PBC) is a chronic nonsuppurative destructive intrahepatic cholangitis leading to cirrhosis after a protractive non cirrhotic stage. The etiology and pathogenesis are largely unknown and autoimmne mechanisms have been implicated to explain the pathological lesions. Many epitopes and autoantigens have been reported as crucial in the pathophysiology of the disease and T and B cells abnormalities have been described, the exact pathways leading to the destruction of small intrahepatic ductules are mostly speculative. In this review we examined the various epidemiologal and geoepidemiological data as well as the complex pathogenetic aspects of this disease, focusing on recent in vivo and in vitro studies in this field. Initiation and progression of PBC is believed to be a multifactorial process with strong infuences from the patient's genetic background and by various environmental factors. The role of innate and adaptive immunity, including cytokines, chemokines, macrophages and the involvement of apoptosis and reactive oxygen species are outlined in detailed. The current pathogenetic aspects are presented and a novel pathogenetic theory unifying the accumulated clinical information with in vitro and in vivo data is formulated.A review of clinical manifestations and immunological and pathological diagnosis was presented. Treatment modalities, including the multiple mechanisms of action of ursodeoxycholate were finally discussed. Core tip: Primary biliary cirrhosis (PBC) is a chronic nonsuppurative destructive intrahepatic cholangitis leading to cirrhosis of largely unknown pathophysiology. We examined the epidemiological and geoepidemiological data as well as the pathogenetic aspects of PBC. A novel pathogenetic theory unifying the accumulated clinical information with in vitro and in vivo data is formulated.

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Enhanced T cell transmigration across the murine liver sinusoidal endothelium is mediated by transcytosis and surface presentation of chemokines†

Cited by 61 publications

References 45 publications

The chemokine receptor CXCR3 limits injury after acute toxic liver damage

The chemokine receptor CXCR3 limits injury after acute toxic liver damage

Tolerance Induction in Response to Liver Inflammation

Primary biliary cirrhosis: From bench to bedside

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