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

Abstract

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.)

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

“…Decreased hepatic NKT cell numbers cor relate with increased local production of proinflammatory T helper 1-associated cytokines [4,5] . We and others have shown that T helper 1-associated cytokines, such as tumor necrosis factor alpha, interleukin 12 and interferon gamma, are significantly elevated in steatotic livers in mouse models of obesity [3][4][5] .…”

“…Decreased hepatic NKT cell numbers cor relate with increased local production of proinflammatory T helper 1-associated cytokines [4,5] . We and others have shown that T helper 1-associated cytokines, such as tumor necrosis factor alpha, interleukin 12 and interferon gamma, are significantly elevated in steatotic livers in mouse models of obesity [3][4][5] . Similar findings have been reported in obese individuals with low levels of adiponectin and increased levels of circulating tumor necrosis factor alpha [6,7] , although those studies did not examine hepatic or peripheral NKT cell numbers.…”

“…NKT cells are unique in their ability to produce both T helper 1-and T helper 2-associated cytokines. The loss of NKT cells likely contributes to disrupted cytokine balance within the liver [5,8,9] . Consistent with their function as a regulator of the immune response, loss of NKT cell-associated interleukin 4 production promotes beta cell destruction in the db/db mouse model of type Ⅰ diabetes [10] .…”

Dietary factors alter hepatic innate immune system in mice with nonalcoholic fatty liver disease

“…6 The depletion of hepatic NKT cells leads to increased local production of proinflammatory (Th-1) cytokines. 7 These cytokines mediate fatty liver vulnerability to LPS in these animals. 7 However, compared with obese humans who have increased levels of leptin, ob/ob mice are genetically leptindeficient and leptin itself is now known to have potent immunomodulatory actions.…”

“…Our previous studies have shown that in genetically obese, leptin-deficient ob/ob mice, 5 natural killer T cells (NKT cells) play important roles in fatty liver vulnerability to LPS. 6,7 NKT cells are components of the innate immune system. They express both T cell surface marker (e.g., CD3) and NK cell surface marker (i.e., NK1.1).…”