Frontline Science: Concanavalin A-induced acute hepatitis is attenuated in vitamin D receptor knockout mice with decreased immune cell function

Abstract

The vitamin D receptor (VDR) is a nuclear receptor for the active form of vitamin D, 1 ,25dihydroxyvitamin D 3 , and regulates various physiologic processes, such as bone and calcium metabolism, cellular proliferation and differentiation, and immunity. VDR is highly expressed in the intestine, kidney, bone, and macrophages, but is expressed at a low level in the liver. The liver is a major metabolic organ and also acts as an immune gateway for dietary nutrients and xenobiotics. In this study, we investigated the function of VDR in hepatic immune cells, such as Kupffer cells/macrophages, utilizing VDR knockout (KO) mice. We showed that VDR is functionally expressed in hepatic mononuclear cells, specifically resident Kupffer cells. We examined the role of VDR in acute hepatitis induced by concanavalin A (Con-A) and found that Con-A-induced hepatitis is attenuated in VDR-KO mice compared to wild-type (WT) mice. Con-A-induced hepatitis is known to be mediated by NKT cell activation, cytokine production, and reactive oxygen species (ROS) production in Kupffer cells/macrophages. However, the proportions of Kupffer cells/macrophages and the NKT cell activation were similar in the liver of WT and VDR-KO mice and inflammatory cytokine gene expression was increased in VDR-KO mice. On the other hand, plasma and hepatic ROS levels were decreased in the liver of VDR-KO mice compared to WT mice.The phagocytic activity of resident Kupffer cells and hepatic neutrophils were also decreased in VDR-KO mice. Therefore, VDR is necessary for Con-A-induced acute hepatitis and plays an important role in hepatic immune cell functions.

The Role and Mechanism of Oxidative Stress and Nuclear Receptors in the Development of NAFLD

“…A new result of a meta-analysis indicated that vitamin D supplementation does not improve glucose metabolism parameters or lipid levels [ 138 ]. Moreover, plasma and hepatic ROS levels are decreased in the liver of VDR-deficiency mice compared to WT mice with acute hepatitis [ 139 ]. Several studies have shown that VDR-knockout mice are resistant to the development of liver steatosis and inflammation by decreasing lipid synthesis and promoting fatty acid oxidation [ 140 ].…”

Contrasting functional responses of resident Kupffer cells and recruited liver macrophages to irradiation and liver X receptor stimulation

“…Concanavalin-A hepatitis, activated resKCs act as the final effectors through TNF-α-induced ROS production [13,14].…”

“…In contrast, concanavalin-A (Con-A) hepatitis is a mouse model of acute hepatic injury induced by NKT cells, recMφs, and resKCs, wherein ROS produced by resKCs are the final effectors [13]. Intriguingly, the vitamin D receptor (VDR), a member of the nuclear receptor superfamily, is highly expressed in resKCs, and VDR KO mice were resistant to Con-A hepatitis due to the resKCs in these mice exhibiting decreased ROS production even under enhanced recMφ TNF-α production [14]. Thus, VDR may differentially regulate the functions of resKCs and recMφs.…”

The upside-downside nature of Vitamin D signaling in liver

“…Animal research has supported the benefits of vitamin D supplementation in a mouse model of AIH . However, data published this month in JLB suggest signaling through the vitamin D receptor (VDR) may actually be detrimental and damaging to the liver in AIH because of increased levels of reactive oxygen species (ROS) . So, are there as many downsides of vitamin D as potential upsides?…”

“…This makes the current study by Umeda et al in this issue of JLB all the more interesting as it suggests that we may need to show some caution before deciding to use vitamin D treatments in AIH patients. In this current study the authors investigated the effects of ConA‐induced hepatitis in a mouse genetically deficient in VDR (VDR −/− ). They found the opposite of what they expected: the VDR −/‐ mice were significantly protected from liver damage and also had reduced ROS levels in liver, with reduced inflammatory cytokines.…”