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


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 alpha. Lentiviral overexpression of Nur77, Nurr1, or NOR-1 reduces expression and production of interleukin (IL)-1beta and IL-6 proinflammatory cytokines and IL-8, macrophage inflammatory protein-1alpha and -1beta 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.


CONCLUSIONS
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.
Bonta
Peter I
PI
Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, The Netherlands.
van Tiel
Claudia M
CM
Vos
Mariska
M
Pols
Thijs W H
TW
van Thienen
Johannes V
JV
Ferreira
Valérie
V
Arkenbout
E Karin
EK
Seppen
Jurgen
J
Spek
C Arnold
CA
van der Poll
Tom
T
Pannekoek
Hans
H
de Vries
Carlie J M
CJ
D050197:Atherosclerosis / Q000378:metabolism* / Q000473:pathology; D018925:Chemokines / Q000037:antagonists & inhibitors; D016207:Cytokines / Q000037:antagonists & inhibitors; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006801:Humans; D007249:Inflammation / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors; D016086:Lentivirus / Q000235:genetics; D050356:Lipid Metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000037:antagonists & inhibitors; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D018925:Chemokines; D016207:Cytokines; D004268:DNA-Binding Proteins; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D008077:Lipoproteins, LDL; D026901:Membrane Transport Proteins; C539821:NR4A1 protein, human; C539882:NR4A2 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; C479458:OSCP1 protein, human; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; C099252:oxidized low density lipoprotein