title: Modulation of Macrophage Gene Expression via Liver X Receptor α 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 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.
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, New York, USA.
authors.forename: Chaowei
authors.initials: C
authors.lastname: Wu
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, New York, USA.
authors.forename: Maryem A
authors.initials: MA
authors.lastname: Hussein
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, New York, USA.
authors.forename: Elina
authors.initials: E
authors.lastname: Shrestha
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, New York, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Leone
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York, USA.
authors.forename: Mohammed S
authors.initials: MS
authors.lastname: Aiyegbo
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, New York, USA.
authors.forename: W Marcus
authors.initials: WM
authors.lastname: Lambert
authors.affiliation: Centre for Clinical Pharmacology, Division of Medicine, University College London, London, United Kingdom.
authors.forename: Benoit
authors.initials: B
authors.lastname: Pourcet
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Cardozo
authors.affiliation: Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, Texas, USA.
authors.forename: Jan-Ake
authors.initials: JA
authors.lastname: Gustafson
authors.affiliation: Department of Medicine, Division of Cardiology, Mark and Ruti Bell Program in Vascular Biology, New York University School of Medicine, New York, New York, USA.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Fisher
authors.affiliation: Centre for Clinical Pharmacology, Division of Medicine, University College London, London, United Kingdom i.torra@ucl.ac.uk michael.garabedian@nyumc.org.
authors.forename: Ines
authors.initials: I
authors.lastname: Pineda-Torra
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, New York, USA i.torra@ucl.ac.uk michael.garabedian@nyumc.org.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Garabedian
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000235:genetics; D002460:Cell Line; D015870:Gene Expression / Q000235:genetics*; D006801:Humans; D008024:Ligands; D000071518:Liver X Receptors; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D057093:Orphan Nuclear Receptors / Q000235:genetics*; D010766:Phosphorylation / Q000235:genetics*; D054400:Receptors, CCR7; D012694:Serine / Q000235:genetics*
chemical_list: D008024:Ligands; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D054400:Receptors, CCR7; D012694:Serine
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