Altered hepatic lymphocyte subpopulations in obesity-related murine fatty livers: Potential mechanism for sensitization to liver damage

Guebre‐Xabier, Mimi; Yang, Shiqi; Lin, Hui-Kuan; Schwenk, Robert; Krzych, Ursula; Diehl, Anna Mae

doi:10.1002/hep.510310313

Cited by 178 publications

(168 citation statements)

References 48 publications

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“…A growing body of experimental data demonstrates a link between hepatosteatosis and defects in NKT numbers and/or function. Over the past years, reductions in NKT cell numbers was reported in the fatty liver by a number of groups including ours [2][3][4] . Observations by our group show an inverse correlation between hepatic NKT cell numbers with the accumulation of hepatic lipid using the choline-deficient diet model of hepatosteatosis [4] .…”

Section: To the Editormentioning

confidence: 73%

“…Observations by our group show an inverse correlation between hepatic NKT cell numbers with the accumulation of hepatic lipid using the choline-deficient diet model of hepatosteatosis [4] . Although different animal models of diet-induced hepatic steatosis using high fat, high sucrose and choline-deficient diet or leptin deficient ob/ob mice showed depletion or decrease in hepatic NKT cell numbers [2][3][4] , it has remained unclear if those findings were relevant to human fatty liver disease.…”

Section: To the Editormentioning

confidence: 99%

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Natural killer T cells and non-alcoholic fatty liver disease: Fat chews on the immune system

Kremer¹,

Hines²

2008

WJG

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Natural killer T cells (NKT) are an important subset of T lymphocytes. They are unique in their ability to produce both T helper 1 and T helper 2 associated cytokines, thus being capable of steering the immune system into either inflammation or tolerance. Disruption of NKT cell numbers or function results in severe deficits in immune surveillance against pathogens and tumor cells. Growing experimental evidence suggests that hepatosteatosis may reduce resident hepatic as well as peripheral NKT cells. Those models of hepatosteatosis and the change in NKT cell numbers are associated with a disruption of cytokine homeostasis, resulting in a more pronounced release of proinflammatory cytokines which renders the steatotic liver highly susceptible to secondary insults. In this letter to the editor, we focus on recently published data in the World Journal of Gastroenterology by Xu and colleagues demonstrating reduced peripheral NKT cells in patients with non-alcoholic fatty liver disease, compare those findings with ours and others in different animal models of hepatosteatosis, and hypothesize about the potential underlying mechanism.

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Section: To the Editormentioning

confidence: 73%

Section: To the Editormentioning

confidence: 99%

Natural killer T cells and non-alcoholic fatty liver disease: Fat chews on the immune system

Kremer¹,

Hines²

2008

WJG

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“…HMNCs were isolated and labeled using a minor modification of the method we described previously. 4 Anti-mouse NK1.1-PE, CD3-FITC, CD4-APC, CD8-PerCP, Annexin-V-PE, and 7-AAD were obtained from Pharmingen (San Diego, CA). After surface labeling, HMNCs were evaluated using flow cytometry (Becton Dickenson, Palo Alto, CA).…”

Section: Methodsmentioning

confidence: 99%

“…3 Previously, we noted that certain populations of liver lymphocytes-specifically natural killer T (NKT) cells-are selectively reduced in the livers of ob/ob mice and suggested that hepatic NKT cell depletion may underlie fatty liver vulnerability to LPS in these animals. 4 NKT cells are components of the innate immune system. These cells originate in the thymus but predominately accumulate in the liver, where they regulate local proinflammatory (T helper [Th]-1) and anti-inflammatory (Th-2) cytokine production by other mononuclear cells.…”

mentioning

confidence: 99%

Norepinephrine regulates hepatic innate immune system in leptin-deficient mice with nonalcoholic steatohepatitis

Oben

Yang

et al. 2004

Hepatology

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It is not known why natural killer T (NKT) cells, which modulate liver injury by regulating local cytokine production, are reduced in leptin-deficient ob/ob mice. NKT cells express adrenoceptors. Thus, we hypothesize that the low norepinephrine (NE) activity of ob/ob mice promotes depletion of liver NKT cells, thereby sensitizing ob/ob livers to lipopolysaccharide (LPS) toxicity. To evaluate this hypothesis, hepatic NKT cells were quantified in wild-type mice before and after treatment with NE inhibitors, and in dopamine ␤-hydroxylase knockout mice (which cannot synthesize NE) and ob/ob mice before and after 4 weeks of NE supplementation. Decreasing NE activity consistently reduces liver NKT cells, while increasing NE has the opposite effect. Analysis of hepatic and thymic NKT cells in mice of different ages demonstrate an age-related accumulation of hepatic NKT cells in normal mice, while liver NKT cells become depleted after birth in ob/ob mice, which have increased apoptosis of hepatic NKT cells. NE treatment inhibits apoptosis and restores hepatic NKT cells. In ob/ob mice with reduced hepatic NKT cells, hepatic T and NKT cells produce excessive T helper (Th)-1 proinflammatory cytokines and the liver is sensitized to LPS toxicity. NE treatment decreases Th-1 cytokines, increases production of Th-2 cytokines, and reduces hepatotoxicity. Studies of CD1d-deficient mice, which lack the receptor required for NKT cell development, demonstrate that they are also unusually sensitive to LPS hepatotoxicity. In conclusion, low NE activity increases hepatic NKT cell apoptosis and depletes liver NKT cells, promoting proinflammatory polarization of hepatic cytokine production that sensitizes the liver to LPS toxicity. (HEPATOLOGY 2004;40:434 -441.)

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“…A recent report demonstrated that ob/ob mice have a deficiency of hepatic NKT cells due to reduced IL-15 and increased IL-12 production by Kupffer cells, 76 and the inability to regulate IL-12 may explain the sensitivity of these animals to endotoxin. 77 However, ob/ob mice are resistant to Con-A-mediated hepatitis, which appears to be related to reduced production of TNF-␣. 78,79 Whether or not a deficiency and functional role of NKT cells are also found in human patients who have nonalcoholic fatty liver disease and excess leptin remains to be determined.…”

Section: Role In Liver Diseasementioning

confidence: 99%

To be or not to be NKT: Natural killer T cells in the liver

2004

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N KT cells are a diverse group of cells that share features of both classical T cells and natural killer (NK) cells, and have similarly diverse functions. One of the complexities in understanding NKT cells involves sorting through the various terminology that has been applied to them in the emerging literature. 1,2 Functionally, a major subset of these cells are defined by reactivity against CD1d, which is one of five known glycolipid-binding nonpolymorphic major histocompatibility complex class 1-like glycoproteins: CD1a through e. 3 These glycoproteins appear to have evolved to facilitate recognition of nonprotein antigens-specifically glycolipid antigens, including those present in the cell walls of mycobacterial species. CD1d is constitutively expressed on a number of hematopoietic-derived antigenpresenting cell (APC) types-including B cells and myeloid cells-and can be expressed by human T cells as well as healthy hepatocytes. Physiological ligands for CD1d remain poorly defined, although both glycolipids and hydrophobic peptides bind to CD1 family molecules. 4,5 Most antigen studies have used the synthetic glycolipid ␣-galactosylceramide (␣GalCer), which binds to CD1d and activates a specific subset of both murine and human NKT cells in vitro and in vivo. 5,6 CD1d is remarkably conserved across mammalian species, with mouse and human CD1d having greater than 90% sequence homology. 7 Consequently, murine CD1d-reactive T cells recognize human CD1d, and vice versa. 8 After activation, NKT cells are highly versatile and can produce large amounts of interferon gamma (IFN-␥) and interleukin (IL)-4 9,10 as prototypic type 1 and type 2 cytokines, respectively, as well as display NK/lymphokine-activated killing-like FasL-mediated or perforin-dependent CD1d-specific cytotoxicity 11-14 thus potentially contributing to protective and pathogenic responses against multiple infectious agents and tumors.CD1d is expressed by dendritic cells (DCs), and ␣Gal-Cer-loaded DCs mediate activation of invariant NKT cells. [15][16][17][18] Although peripheral NKT cells can recognize and respond to other CD1d ϩ cells, their in vivo activation may be initiated by interactions with DCs and possibly B cells. The interactions between invariant NKT cells and DCs share many features of interactions between conventional CD4 ϩ T cells and DCs. DCs pulsed with ␣GalCer stimulate NKT cells through T cell receptor (TCR) ligation. 2,19,20 NKT cell activation and IFN-␥ production are markedly enhanced by DC-produced IL-12, with an increase in the IL-12 receptor on activated NKT cells. 15,21,22 Conversely, invariant NKT cells also interact with ␣Gal-Cer-loaded DCs to enhance CD4 ϩ and CD8 ϩ T-cell responses 16,17,23,24 and with B cells to provide help for antibody production. 25 However, ␣Galcer is not a physiological antigen, and it is not yet clear whether physiological NKT-DC interactions are mediated by specific CD1d-presented antigens or are antigen independent.The classical CD1d-reactive NKT cell population expresses a highly restricted TCR r...

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Altered hepatic lymphocyte subpopulations in obesity-related murine fatty livers: Potential mechanism for sensitization to liver damage

Cited by 178 publications

References 48 publications

Natural killer T cells and non-alcoholic fatty liver disease: Fat chews on the immune system

Natural killer T cells and non-alcoholic fatty liver disease: Fat chews on the immune system

Norepinephrine regulates hepatic innate immune system in leptin-deficient mice with nonalcoholic steatohepatitis

To be or not to be NKT: Natural killer T cells in the liver

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