Lack of Chemokine Receptor CCR5 Promotes Murine Fulminant Liver Failure by Preventing the Apoptosis of Activated CD1d-Restricted NKT Cells

Ajuebor, Maureen N.; Aspinall, Alexander I.; Zhou, Feng; Le, Tai; Yang, Yang; Urbanski, Stefan J.; Sidobre, Stéphane; Kronenberg, Mitchell; Hogaboam, Cory M.; Swain, Mark G.

doi:10.4049/jimmunol.174.12.8027

Cited by 72 publications

(116 citation statements)

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“…The depletion of NKT cells during liver fibrosis progression has been observed previously (12) and could be related to either activation-induced NKT cell death or loss of cell markers such as NK1.1 (38,41,42). In the CCl 4 fibrosis model, NKT cell apoptosis in particular was found to account for reduced NKT cell numbers in chronic injury (12), and it had been speculated that the depletion of NKT cells abrogated their beneficial effects on stellate cells.…”

Section: Discussionmentioning

confidence: 96%

“…Their role in the pathogenesis of chronic liver injury and fibrosis is controversial. Experimental studies using Con A or a-GalCer demonstrated that NKT cell activation contributes to acute hepatitis (15,16,38), likely by releasing various proinflammatory cytokines and via Fas-mediated cell lysis (4). In HBVtransgenic mice, NKT cell activation promoted fibrosis progres- sion by secreting HSC-activating cytokines IL-4 and IL-13 (39), similar to observations from patients with chronic hepatitis B (40) and consistent with the cytokine expression pattern we identified in hepatic NKT cells isolated from murine injury models in WT, but not Cxcr6 2/2 mice.…”

Section: Discussionmentioning

confidence: 99%

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Chemokine Receptor CXCR6-Dependent Hepatic NK T Cell Accumulation Promotes Inflammation and Liver Fibrosis

Wehr

Baeck

Heymann

et al. 2013

The Journal of Immunology

227

198

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Chronic liver injury characteristically results in hepatic inflammation, which represents a prerequisite for organ fibrosis. Although NKT cells are abundantly present in liver and involved in hepatic inflammation, molecular mechanisms of their recruitment in liver fibrosis remained elusive. We hypothesized that chemokine receptor CXCR6 and its ligand CXCL16 control NKT cell migration and functionality in liver fibrosis. In patients with chronic liver diseases (n = 58), CXCR6 and CXCL16 expression was intrahepatically upregulated compared with controls. In murine liver, Cxcl16 was strongly expressed by endothelium and macrophages, whereas lymphocyte populations (NKT, NK, CD4 T, CD8 T cells) expressed CXCR6. Intravital two-photon microscopy imaging of Cxcr6+/gfp and Cxcr6gfp/gfp mice and chemotaxis studies in vitro revealed that CXCR6 specifically controls hepatic NKT cell accumulation during the early response upon experimental liver damage. Hepatic invariant NKT cells expressed distinct proinflammatory cytokines including IFN-γ and IL-4 upon injury. CXCR6-deficient mice were protected from liver fibrosis progression in two independent experimental models. Macrophage infiltration and protein levels of inflammatory cytokines IFN-γ, TNF-α, and IL-4 were also reduced in fibrotic livers of Cxcr6−/− mice, corroborating that hepatic NKT cells provide essential cytokine signals perpetuating hepatic inflammation and fibrogenesis. Adoptive transfer of NKT cells, but not CD4 T cells, isolated from wild type livers restored hepatic fibrosis in Cxcr6−/− mice upon experimental steatohepatitis. Our results demonstrate that hepatic NKT cells accumulate CXCR6-dependent early upon injury, thereby accentuating the inflammatory response in the liver and promoting hepatic fibrogenesis. Interfering with CXCR6/CXCL16 might therefore bear therapeutic potential in liver fibrosis.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Chemokine Receptor CXCR6-Dependent Hepatic NK T Cell Accumulation Promotes Inflammation and Liver Fibrosis

Wehr

Baeck

Heymann

et al. 2013

The Journal of Immunology

227

198

View full text Add to dashboard Cite

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“…6C. Although NKT cells rapidly disappeared after ConA stimulation for activation-induced cell death, 14,18 cytokines secreted by NKT cells might exert a function (Fig. 6C).…”

Section: Help Function Of Nkt Cells In Nk Cell-mediatedmentioning

confidence: 99%

Increased susceptibility to liver injury in hepatitis B virus transgenic mice involves NKG2D-ligand interaction and natural killer cells

et al. 2007

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“…For example activation of chemokine receptors promotes apoptosis in neurons and T cells as well as survival of glioblastoma, ovarian carcinoma, pancreatic adenocarcinoma and other cancer cells. [10][11][12] These previous data linking some chemokine receptors with apoptosis and the correlation between functional activation of CXCR4 and CCR7 and an invasive, metastatic phenotype of breast cancer cells together with the ability of these receptors to induce cytoskeletal changes have led us to hypothesize that CXCR4 and CCR7 may influence cancer cell metastasis by regulating detachment-induced apoptosis. We describe here a novel common role for CXCR4 and CCR7 in inhibiting anoikis, specifically in metastatic breast cancer cells.…”

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confidence: 99%

Chemokine receptors CXCR4 and CCR7 promote metastasis by preventing anoikis in cancer cells

2009

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Chemokine receptors are essential mediators of the metastatic spread in various cancer types; however their precise function in the development of secondary tumors remains poorly understood. We report here a novel property of the chemokine receptors CXCR4 and CCR7 in inhibiting detachment-induced cell death -anoikis, which is believed to be one of the major blocks in the metastatic spread of various neoplasms. Activation of these chemokine receptors by their respective ligands, CXCL12 and CCL21 specifically reduced the sensitivity of metastatic breast cancer cells to anoikis by a distinct mechanism of selective regulation of pro-apoptotic Bmf and anti-apoptotic Bcl-xL proteins. Consequently, functional CXCR4 and CCR7 increased cell survival in the absence of correct ECM attachment both in vitro and in vivo. We also demonstrated that preventing chemokineinduced reduction in Bmf levels significantly attenuated breast cancer metastasis in an experimental mouse model. These results provide evidence for a previously unknown axis in malignant tumors, which connects chemokine receptors with deregulated apoptosis in the absence of the appropriate cell -ECM interaction and may offer novel targets for therapeutic intervention for the treatment of metastatic breast and potentially other tumors. Cell Death and Differentiation (2009) 16, 664-673; doi:10.1038/cdd.2008; published online 9 January 2009The main cause of cancer-related deaths is the spread of tumor cells to sites distant from the primary locus and the subsequent establishment of secondary lesions. The heterogeneity and complexity of malignant transformation make it difficult to identify common molecular mechanisms governing the metastatic progression of cancer and potentially account for the lack of effective treatments for malignant cancers. Recently, members of the chemokine receptor family of G-protein-coupled receptors (GPCRs) have been assigned a major role in this process (reviewed in Zlotnik 1 ). It is becoming increasingly clear that many members of this family regulate a complex milieu of interactions between tumor cells, stromal cells, tumor infiltrating leukocytes and endothelial cells and that better understanding of the specific actions of chemokines and their receptors in promoting malignancy will significantly contribute to combating cancer. 2 CXCR4 and CCR7 are the major chemokine receptors found on a wide range of tumor cells and high levels of these receptors are associated with higher grade and poor prognosis of breast, lung, colon and other cancers. 3 Blocking the interaction between CXCR4 and its ligand CXCL12, dramatically reduces breast and other cancer metastases in mouse models. 4 Our recent results have also provided a direct correlation between functional activation of CXCR4 and CCR7 and the invasive, metastatic phenotype of breast cancer cells 5 further supporting a highly important role for these molecules in tumor dissemination to distant sites. Initial studies suggested that these surface molecules induce directional migration of ma...

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Lack of Chemokine Receptor CCR5 Promotes Murine Fulminant Liver Failure by Preventing the Apoptosis of Activated CD1d-Restricted NKT Cells

Cited by 72 publications

References 54 publications

Chemokine Receptor CXCR6-Dependent Hepatic NK T Cell Accumulation Promotes Inflammation and Liver Fibrosis

Chemokine Receptor CXCR6-Dependent Hepatic NK T Cell Accumulation Promotes Inflammation and Liver Fibrosis

Increased susceptibility to liver injury in hepatitis B virus transgenic mice involves NKG2D-ligand interaction and natural killer cells

Chemokine receptors CXCR4 and CCR7 promote metastasis by preventing anoikis in cancer cells

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