Liver X receptors regulate hepatic F4/80 + CD11b+ Kupffer cells/macrophages and innate immune responses in mice

Abstract

The liver X receptors (LXRs), LXRα and LXRβ, are nuclear receptors that regulate lipid homeostasis. LXRs also regulate inflammatory responses in cultured macrophages. However, the role of LXRs in hepatic immune cells remains poorly characterized. We investigated the role of LXRs in regulation of inflammatory responses of hepatic mononuclear cells (MNCs) in mice. Both LXRα and LXRβ were expressed in mouse hepatic MNCs and F4/80+ Kupffer cells/macrophages. LXRα/β-knockout (KO) mice had an increased number of hepatic MNCs and elevated expression of macrophage surface markers and inflammatory cytokines compared to wild-type (WT) mice. Among MNCs, F4/80+CD11b+ cells, not F4/80+CD11b− or F4/80+CD68+ cells, were increased in LXRα/β-KO mice more than WT mice. Isolated hepatic MNCs and F4/80+CD11b+ cells of LXRα/β-KO mice showed enhanced production of inflammatory cytokines after stimulation by lipopolysaccharide or CpG-DNA compared to WT cells, and LXR ligand treatment suppressed lipopolysaccharide-induced cytokine expression in hepatic MNCs. Lipopolysaccharide administration also stimulated inflammatory cytokine production in LXRα/β-KO mice more effectively than WT mice. Thus, LXR deletion enhances recruitment of F4/80+CD11b+ Kupffer cells/macrophages and acute immune responses in the liver. LXRs regulate the Kupffer cell/macrophage population and innate immune and inflammatory responses in mouse liver.

PNPLA3 I148M Variant Impairs Liver X Receptor Signaling and Cholesterol Homeostasis in Human Hepatic Stellate Cells

“…Considering the capacity of LXRs to repress release of inflammatory mediators in macrophages, the role of these nuclear receptors strongly leads to a link between hepatic metabolism and immune response. Liver resident macrophages lacking LXRs underline that the latter control the differentiation of the Kupffer cell population and regulate immune and inflammatory responses in mice . The activation and overexpression of LXRα following ROSI stimulation provides a direct anti‐inflammatory effect on cytokine expression in HSCs carrying the WT along with no detectable improvement in cells with the PNPLA3 variant (Fig.…”

“…Remarkably, the two LXR isotypes display distinct function and tissue distribution throughout the body; β is ubiquitously expressed, whereas α is restricted to metabolic organs . In the liver, transcripts of LXRα and LXRβ were found in both parenchymal and nonparenchymal cells . LXRs have received considerable attention as possible candidates for therapeutic approaches in metabolic diseases due to LXRα‐mediated induction of bile acid synthesis, hepatic de novo lipogenesis, and reduction of high‐density lipoprotein cholesterol in LXRα knockout (KO) mice .…”

Activation of Liver X Receptor α Sensitizes Mice to T‐Cell Mediated Hepatitis

“…(23,24) Meanwhile, activation of LXRs have been shown to suppress the production of inflammatory cytokines by KCs. (25)(26)(27) We therefore wanted to determine whether KCs are involved in the effect of LXRα activation or ablation on ConA-induced hepatitis. Treatment with GdCl 3 was used to deplete KCs, (23) and the depletion efficiency was confirmed by the decreased hepatic expression of KC marker gene F4/80 (Fig.…”

Understanding the Impact of Dietary Cholesterol on Chronic Metabolic Diseases through Studies in Rodent Models

“…Interestingly, genetic inactivation of LXRα/β in mice increased the number of proinflammatory F4/80+CD11b+ macrophages in the liver, suggesting that deranged cholesterol homeostasis that affects LXR might directly activate inflammatory pathways and immune responses [ 43 ].…”