Abstract
In the murine liver, there are two major macrophage populations, namely resident Kupffer cells (resKCs) with phagocytic activity and recruited macrophages (recMφs) with cytokine-producing capacity. This study was performed to clarify the functional differences between these two populations, focusing on their susceptibility to radiation and response to stimulation via liver X receptors (LXRs), which are implicated in cholesterol metabolism and immune regulation. Liver mononuclear cells (MNCs) were obtained from C57BL/6 (WT) mice with or without 2 Gy irradiation, and the phagocytic activity against Escherichia coli (E. coli) as well as TNF-α production were compared between the two macrophage populations. To assess LXR functions, phagocytosis, TNF-α production, and endocytosis of acetylated low-density lipoprotein (LDL) were compared after synthetic LXR ligand stimulation. Furthermore, LXRα/β knockout (KO) mice and LXRα KO mice were compared with WT mice. Irradiation decreased intracellular TNF-α production by recMφs but did not affect the phagocytic activity of resKCs. In vitro LXR stimulation enhanced E. coli phagocytosis by resKCs but decreased E. coli-stimulated TNF-α production by recMφs. Phagocytic activity and acetylated LDL endocytosis were decreased in both LXRα/β KO mice and LXRα KO mice, with serum TNF-α levels after E. coli injection in the former being higher than those in WT mice. In conclusion, resKCs and recMφs exhibited different functional features in response to radiation and LXR stimulation, highlighting their distinct roles liver immunity and lipid metabolism.
Highlights
Various innate immune cell types can be found in the liver, including natural killer (NK) cells, natural killer T (NKT) cells, and macrophages
vitamin D receptor (VDR) may differentially regulate the functions of resident Kupffer cells (resKCs) and recMφs. These findings suggest that nuclear receptors, including liver X receptors (LXRs), may be linked to metabolism and immune function in the liver through Kupffer cells/ macrophages
RecMφs in each group of mice endocytosed a small amount of acetylated low-density lipoprotein (LDL) (Fig 6A upper panels and Fig 6B blue columns, n = 5). These results suggested that LXRα deletion may impair LDL endocytosis in resKCs and subsequently reduce the hydrolysis of cholesterol esters and triglycerides in the phagolysosomes of resKCs [25], suggesting that lipogenesis was impaired in LXR KO mice
Summary
Various innate immune cell types can be found in the liver, including natural killer (NK) cells, natural killer T (NKT) cells, and macrophages. VDR may differentially regulate the functions of resKCs and recMφs These findings suggest that nuclear receptors, including LXRs, may be linked to metabolism and immune function in the liver through Kupffer cells/ macrophages. LXRα is preferentially expressed in the liver, adipose tissue, and macrophages, whereas LXRβ is widely present throughout the body [15] Both LXRs are activated by oxysterols, such as 24,25(S)-epoxycholesterol and 22(R)-hydroxycholesterol, and regulate the expression of genes involved in cholesterol and lipid metabolism, such as ATPbinding cassette A1, cholesterol 7α-hydroxylase, and sterol regulatory element-binding protein 1c (SREBP-1c) [16]. We sought to elucidate how irradiation and LXR affect the functions of liver recMφs and resKCs, including bacteria phagolytic activity, cytokine production, and LDL endocytosis
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