Modulation of macrophage gene expression via liver X receptor α serine 198 phosphorylation

Chaowei Wu, Maryem A. Hussein, Elina Shrestha, Sarah Leone, Mohammed S. Aiyegbo, W. Marcus Lambert, Benoit Pourcet, Timothy Cardozo, Jan Ake Gustafson, Edward A. Fisher, Ines Pineda-Torra, Michael J. Garabedian

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

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 LXRα 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 LXRα at S198 is nonphosphorylated. In bone marrow-derived macrophages (BMDMs), we also observed induction of CCR7 by ligands that promote nonphosphorylated LXRα S198, and this was lost in LXR-deficient BMDMs. LXRα occupancy at the CCR7 promoter is enhanced and histone modifications associated with gene repression are reduced in RAW264.7 cells expressing nonphosphorylated LXRα (RAW-LXRα S198A) compared to RAW264.7 cells expressing wild-type (WT) phosphorylated LXRα (RAW-LXRα WT). Expression profiling of ligand-treated RAW-LXRα S198A cells compared to RAW-LXRα WT cells revealed induction of cell migratory and anti-inflammatory genes and repression of proinflammatory genes. Modeling of LXRα 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 LXRα S198 phosphorylation, including that of antiatherogenic genes such as CCR7.

Original languageEnglish (US)
Pages (from-to)2024-2034
Number of pages11
JournalMolecular and Cellular Biology
Volume35
Issue number11
DOIs
StatePublished - 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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