Modulation of Macrophage Gene Expression via Liver X Receptor ? Serine 198 Phosphorylation.

ABSTRACT: In mouse models of atherosclerosis, normalization of hyperlipidemia promotes macrophage emigration and regression of atherosclerotic plaques in part by liver X receptor (LXR)-mediated induction of the chemokine receptor CCR7. Here we report that LXR? serine 198 (S198) phosphorylation modulates CCR7 expression. Low levels of S198 phosphorylation are observed in plaque macrophages in the regression environment where high levels of CCR7 expression are observed. Consistent with these findings, CCR7 gene expression in human and mouse macrophages cell lines is induced when LXR? at S198 is nonphosphorylated. In bone marrow-derived macrophages (BMDMs), we also observed induction of CCR7 by ligands that promote nonphosphorylated LXR? S198, and this was lost in LXR-deficient BMDMs. LXR? occupancy at the CCR7 promoter is enhanced and histone modifications associated with gene repression are reduced in RAW264.7 cells expressing nonphosphorylated LXR? (RAW-LXR? S198A) compared to RAW264.7 cells expressing wild-type (WT) phosphorylated LXR? (RAW-LXR? WT). Expression profiling of ligand-treated RAW-LXR? S198A cells compared to RAW-LXR? WT cells revealed induction of cell migratory and anti-inflammatory genes and repression of proinflammatory genes. Modeling of LXR? S198 in the nonphosphorylated and phosphorylated states identified phosphorylation-dependent conformational changes in the hinge region commensurate with the presence of sites for protein interaction. Therefore, gene transcription is regulated by LXR? S198 phosphorylation, including that of antiatherogenic genes such as CCR7.

SUBMITTER: Wu C 

PROVIDER: S-EPMC4420924 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature