Nuclear receptors Nur77, Nurr1, and NOR-1 expressed in atherosclerotic lesion macrophages reduce lipid loading and inflammatory responses

Peter I. Bonta, Claudia M. Van Tiel, Mariska Vos, Thijs W.H. Pols, Johannes V. Van Thienen, Valérie Ferreira, E. Karin Arkenbout, Jurgen Seppen, C. Arnold Spek, Tom Van Der Poll, Hans Pannekoek, Carlie J.M. De Vries

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Abstract

OBJECTIVE - Atherosclerosis is an inflammatory disease in which macrophage activation and lipid loading play a crucial role. In this study, we investigated expression and function of the NR4A nuclear receptor family, comprising Nur77 (NR4A1, TR3), Nurr1 (NR4A2), and NOR-1 (NR4A3) in human macrophages. METHODS AND RESULTS - Nur77, Nurr1, and NOR-1 are expressed in early and advanced human atherosclerotic lesion macrophages primarily in areas of plaque activation/progression as detected by in situ-hybridization and immunohistochemistry. Protein expression localizes to the nucleus. Primary and THP-1 macrophages transiently express NR4A-factors in response to lipopolysaccharide and tumor necrosis factor α. Lentiviral overexpression of Nur77, Nurr1, or NOR-1 reduces expression and production of interleukin (IL)-1β and IL-6 proinflammatory cytokines and IL-8, macrophage inflammatory protein-1α and -1β and monocyte chemoattractant protein-1 chemokines. In addition, NR4A-factors reduce oxidized-low-density lipoprotein uptake, consistent with downregulation of scavenger receptor-A, CD36, and CD11b macrophage marker genes. Knockdown of Nur77 or NOR-1 with gene-specific lentiviral short-hairpin RNAs resulted in enhanced cytokine and chemokine synthesis, increased lipid loading, and augmented CD11b expression, demonstrating endogenous NR4A-factors to inhibit macrophage activation, foam-cell formation, and differentiation. CONCLUSION - NR4A-factors are expressed in human atherosclerotic lesion macrophages and reduce human macrophage lipid loading and inflammatory responses, providing further evidence for a protective role of NR4A-factors in atherogenesis.

Original languageEnglish
Pages (from-to)2288-2294
Number of pages7
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume26
Issue number10
DOIs
Publication statusPublished - Oct 2006

Keywords

  • Atherosclerosis
  • Foam-cell formation
  • Inflammation
  • Macrophage function
  • NR4A
  • Nuclear orphan receptors

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