Abstract
We have reported that the mouse hepatic injury induced by either α-galactosylceramide (α-GalCer) or bacterial DNA motifs (CpG-ODN) is mediated by the TNF/NKT cell/Fas-ligand (FasL) pathway. In addition, F4/80+ Kupffer cells can be subclassified into CD68+ subset with a phagocytosing capacity and CD11b+ subset with a TNF-producing capacity. CD11b+ subset increase if mice are fed high-fat and cholesterol diet (HFCD). The present study examined how a HFCD affects the function of NKT cells and F4/80+ CD11b+ subset and these hepatitis models. After the C57BL/6 mice received a HFCD, high-cholesterol diet (HCD), high-fat diet (HFD) and control diet (CD) for four weeks, the HFCD mice increased surface CD1d and intracellular TLR-9 expression by the CD11b+ population compared to CD mice. Hepatic injury induced either by α-GalCer or CpG-ODN was more severe in HCD and HFCD mice compared to CD mice, which was in proportion to the serum TNF levels. In addition, liver cholesterol levels but not serum cholesterol levels nor liver triglyceride levels were involved in the aggravation of hepatitis. The FasL expression of NKT cells induced by both reagents was upregulated in HFCD mice. Furthermore, the liver mononuclear cells and purified F4/80+ CD11b+ subset from HFCD mice stimulated with either reagent in vitro produced a larger amount of TNF than did those from CD mice. Intracellular TNF production in F4/80+ CD11b+ cells was confirmed. The increased number of F4/80+ CD11b+ Kupffer cells/macrophages by HFCD and their enhanced TNF production thus play a pivotal role in TNF/NKT cell/FasL dependent hepatic injury.
Highlights
The liver has a large number of macrophage lineage cells, Kupffer cells, which make up 80% of the total body macrophages [1,2,3]
We investigated how a high-fat and cholesterol diet (HFCD) affects the function of CD11b+ Kupffer cells, natural killer T (NKT) cells and TNF/FasLdependent hepatitis evoked by these cells, and discuss the possible role of these cells in human non-alcoholic steatohepatitis (NASH)
Production of intracellular TNF by CD11b+ Kupffer cells In addition to control diet (CD) mice and HFCD mice, mice fed HFCD for 3 months were used, because we previously reported that serum TNF levels after a-GalCer injection increased in an age dependent manner [16]. 30 min after a-GalCer injection, liver mononuclear cells (MNCs) were obtained without collagenase treatment. 3.8% in CD11b+ cells in CD mice expressed intracellular TNF (Fig. 10), 18.0% in F4/80/ CD11b+ cells in HFCD mice expressed intracellular TNF (Fig. 10)
Summary
The liver has a large number of macrophage lineage cells, Kupffer cells, which make up 80% of the total body macrophages [1,2,3]. Mouse liver mononuclear cells (MNCs) have large proportion of innate immune lymphocytes, comprising NK cells (10–20%) and natural killer T (NKT) cells (15–25%) [2,3]. These innate immune cells in the liver normally play a pivotal role in the host defense against microbes and tumors via the T helper 1 immune response [2,4,5]. We previously reported that mouse liver NKT cells activated by a-GalCer (a synthetic glycolipid and NKT cell ligand) express Fas-ligand (FasL) and induce hepatocyte injury in a TNF/ FasL-dependent manner [4,5]. NKT cells activated by a Toll-like receptor-9 (TLR-9) agonist common bacterial DNA motifs (CpGODN) [7,8] induce hepatic injury in a TNF/FasL-dependent manner [9], which is inhibited in NKT cell-deficient mice [9]
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