Diverse roles of invariant natural killer T cells in liver injury and fibrosis induced by carbon tetrachloride

Park, Ogyi; Jeong, Won Il; Wang, Lei; Wang, Hua; Lian, Zhe Xiong; Gershwin, M. Eric; Gao, Bin

doi:10.1002/hep.22813

Cited by 171 publications

(183 citation statements)

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“…In line with the observations during acute injury (Fig.3), fibrotic livers of WT mice showed increased macrophage numbers compared with Cxcr6 2/2 mice, whereas NKT cells were low in the livers of all chronically injured animals ( Fig. 4C-E), confirming previous results that hepatic NKT cell numbers are strongly decreased in established CCl 4 -induced liver fibrosis mostly because of NKT cell apoptosis (12). Other hepatic lymphocyte populations (NK, CD4 T, and CD8 T cells) did not differ in cell frequency or cell numbers between WT and Cxcr6 2/2 mice in CCl 4 -induced liver fibrosis (Supplemental Fig.…”

Section: Cxcr6 Controls Hepatic Nkt Cell Accumulation Upon Experimentssupporting

confidence: 91%

“…As anticipated from prior studies, the NKT cell pool decreased subsequently (Fig. 3C) because of an overwhelming influx of monocytes-macrophages and apoptosis of activated NKT cells (12,28). In contrast, hepatic NKT cells were dramatically reduced already at baseline in Cxcr6 2/2 mice, and the distinct accumulation of hepatic NKT cells could not be established in injured liver in the absence of CXCR6 (Fig.…”

Section: Cxcr6 Controls Hepatic Nkt Cell Accumulation Upon Experimentssupporting

confidence: 76%

“…In addition, CD8 T cells endorse liver fibrosis via activating hepatic stellate cells (HSC) (9), whereas NK cells are capable of promoting HSC apoptosis and are thus considered antifibrotic (10,11). The functional role of NKT cells, which are abundantly present in the liver and constitute ∼30% of the hepatic lymphocytes, in liver fibrogenesis is less clear (12,13).…”

mentioning

confidence: 99%

“…Upon activation, NKT cells can produce a variety of different cytokines, including IFN-g and IL-4. However, most experimental data indicate that NKT cells undergo activation-induced cell death within hours after stimulation, such as with CD3-specific Ab or a-GalCer (17), resulting in low hepatic NKT cell numbers in chronic injury, such as fibrosis (12). In experimental models, Cd1d 2/2 mice lacking NKT cells were less susceptible to inflammation, hepatocyte apoptosis, and fibrosis (18,19).…”

mentioning

confidence: 99%

“…Concordantly, the preactivation of hepatic NKT cells by a-GalCer accelerated liver fibrosis in experimental murine models (12). However, particularly in early phases of carbon tetrachloride (CCl 4 )-induced fibrosis, NKT cells can also be protective by restricting HSC activation, suggesting that the net effect of NKT cells in liver scarring depends on the balance between protective and detrimental consequences of NKT cell activation (12,20).…”

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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: Cxcr6 Controls Hepatic Nkt Cell Accumulation Upon Experimentssupporting

confidence: 91%

Section: Cxcr6 Controls Hepatic Nkt Cell Accumulation Upon Experimentssupporting

confidence: 76%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

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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Murine iNKT cells are depleted by liver damage via activation of P2RX7

et al. 2020

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Invariant natural killer T cells (iNKT) constitute up to 50% of liver lymphocytes and contribute to immunosurveillance as well as pathogenesis of the liver. Systemic activation of iNKT cells induces acute immune-mediated liver injury. However, how tissue damage events regulate iNKT cell function and homeostasis remains unclear. We found that specifically tissue-resident iNKT cells in liver and spleen express the tissue-damage receptor P2RX7 and the P2RX7-activating ectoenzyme ARTC2. P2RX7 expression restricted formation of iNKT cells in the liver suggesting that liver iNKT cells are actively restrained under homeostatic conditions. Deliberate activation of P2RX7 in vivo by exogenous NAD resulted in a nearly complete iNKT cell ablation in liver and spleen in a P2RX7-dependent manner. Tissue damage generated by acetaminophen-induced liver injury reduced the number of iNKT cells in the liver. The tissue-damage-induced iNKT cell depletion was driven by P2RX7 and localized to the site of injury, as iNKT cells in the spleen remained intact. The depleted liver iNKT cells reconstituted only slowly compared to other lymphocytes such as regulatory T cells. These findings suggest that tissue-damage-mediated depletion of iNKT cells acts as a feedback mechanism to limit iNKT cell-induced pathology resulting in the establishment of a tolerogenic environment.

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Hines

2009

Hepatology

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ducers of IL13, it would be of interest to ascertain if IL12 knockout mice express different amounts of IL13.Reductions in both NKT and NK cells occurred in choline-deficientdiet mice and individuals with hepatic steatosis. However, when cholinedeficient-diet mice were inoculated with clodronate-containing liposomes, they exhibited four-fold reductions in NK cells (and lower IL12) while maintaining NKT numbers. In contrast, control-treated mice preserved their NK population (and increased IL12) while reducing NKT numbers (a reversal of NK: NKT ratios) 1 . NK cells secrete IFN-␥ and have been shown to inhibit fibrosis. 8 Future work is needed to delineate the relationship between NKT and NK populations in progressive liver disease and determine if different NKT subsets affect disease outcomes.

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Diverse roles of invariant natural killer T cells in liver injury and fibrosis induced by carbon tetrachloride

Cited by 171 publications

References 48 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

Murine iNKT cells are depleted by liver damage via activation of P2RX7

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