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

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.