The neuron-derived orphan receptor 1 (NOR1) is induced upon human alternative macrophage polarization and stimulates the expression of markers of the M2 phenotype.
BACKGROUND
Atherosclerosis is an inflammatory disease in which macrophages play a crucial role. Macrophages are present in different phenotypes, with at the extremes of the spectrum the classical M1 pro-inflammatory and the alternative M2 anti-inflammatory macrophages. The neuron-derived orphan receptor 1 (NOR1), together with Nur77 and Nurr1, are members of the NR4A orphan nuclear receptor family, expressed in human atherosclerotic lesion macrophages. However, the role of NOR1 in human macrophages has not been studied yet.


OBJECTIVE
To determine the expression and the functions of NOR1 in human alternative macrophages.


RESULTS
In vitro IL-4 polarization of primary monocytes into alternative M2 macrophages enhances NOR1 expression in human but not in mouse macrophages. Moreover, NOR1 expression is most abundant in CD68+MR+ alternative macrophage-enriched areas of human atherosclerotic plaques in vivo. Silencing NOR1 in human alternative macrophages decreases the expression of several M2 markers such as the Mannose Receptor (MR), Interleukin-1 Receptor antagonist (IL-1Ra), CD200 Receptor (CD200R), coagulation factor XIII A1 polypeptide (F13A1), Interleukin 10 (IL-10) and the Peroxisome Proliferator-Activated Receptor (PPAR)γ. Bioinformatical analysis identified F13A1, IL-1Ra, IL-10 and the Matrix Metalloproteinase-9 (MMP9) as potential target genes of NOR1 in human alternative macrophages. Moreover, expression and enzymatic activity of MMP9 are induced by silencing and repressed by NOR1 overexpression in M2 macrophages.


CONCLUSIONS
These data identify NOR1 as a transcription factor induced during alternative differentiation of human macrophages and demonstrate that NOR1 modifies the alternative macrophage phenotype.
Université Lille 2, F-59000 Lille, France; Inserm, U1011, F-59000 Lille, France; Institut Pasteur de Lille, F-59019 Lille, France; European Genomic Institute for Diabetes (EGID), FR 3508, F-59000 Lille, France.
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De Paoli
Université Lille 2, F-59000 Lille, France; Inserm, U1011, F-59000 Lille, France; Institut Pasteur de Lille, F-59019 Lille, France; European Genomic Institute for Diabetes (EGID), FR 3508, F-59000 Lille, France.
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Eeckhoute
Université Lille 2, F-59000 Lille, France; Inserm, U1011, F-59000 Lille, France; Institut Pasteur de Lille, F-59019 Lille, France; European Genomic Institute for Diabetes (EGID), FR 3508, F-59000 Lille, France.
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Copin
Université Lille 2, F-59000 Lille, France; Inserm, U1011, F-59000 Lille, France; Institut Pasteur de Lille, F-59019 Lille, France; European Genomic Institute for Diabetes (EGID), FR 3508, F-59000 Lille, France.
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Vanhoutte
Université Lille 2, F-59000 Lille, France; Inserm, U1011, F-59000 Lille, France; Institut Pasteur de Lille, F-59019 Lille, France; European Genomic Institute for Diabetes (EGID), FR 3508, F-59000 Lille, France.
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Duhem
Université Lille 2, F-59000 Lille, France; Inserm, U1011, F-59000 Lille, France; Institut Pasteur de Lille, F-59019 Lille, France; European Genomic Institute for Diabetes (EGID), FR 3508, F-59000 Lille, France.
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Derudas
Université Lille 2, F-59000 Lille, France; Inserm, U1011, F-59000 Lille, France; Institut Pasteur de Lille, F-59019 Lille, France; European Genomic Institute for Diabetes (EGID), FR 3508, F-59000 Lille, France.
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Dubois-Chevalier
Université Lille 2, F-59000 Lille, France; Inserm, U1011, F-59000 Lille, France; Institut Pasteur de Lille, F-59019 Lille, France; European Genomic Institute for Diabetes (EGID), FR 3508, F-59000 Lille, France.
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Colin
Université Lille 2, F-59000 Lille, France; Centre Hospitalier Régional Universitaire de Lille, France.
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Zawadzki
Université Lille 2, F-59000 Lille, France; Centre Hospitalier Régional Universitaire de Lille, France.
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Jude
Centre Hospitalier Régional Universitaire de Lille, France.
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Haulon
Université Lille 2, F-59000 Lille, France; Inserm, U1011, F-59000 Lille, France; Institut Pasteur de Lille, F-59019 Lille, France; European Genomic Institute for Diabetes (EGID), FR 3508, F-59000 Lille, France.
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Lefebvre
Université Lille 2, F-59000 Lille, France; Inserm, U1011, F-59000 Lille, France; Institut Pasteur de Lille, F-59019 Lille, France; European Genomic Institute for Diabetes (EGID), FR 3508, F-59000 Lille, France. Electronic address: bart.staels@pasteur-lille.fr.
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Staels
Université Lille 2, F-59000 Lille, France; Inserm, U1011, F-59000 Lille, France; Institut Pasteur de Lille, F-59019 Lille, France; European Genomic Institute for Diabetes (EGID), FR 3508, F-59000 Lille, France; INSERM, U 1081, Institute for Research on Cancer and Aging of Nice (IRCAN), "Aging and Diabetes" team, France; University of Nice-Sophia Antipolis, Nice, France; Clinical Chemistry Laboratory, University Hospital, Nice, France.
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Chinetti-Gbaguidi
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002340:Carotid Artery Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020868:Gene Silencing; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D015847:Interleukin-4 / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D010641:Phenotype; D058226:Plaque, Atherosclerotic; D061251:Primary Cell Culture; D034622:RNA Interference; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000378:metabolism*; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection
D015415:Biomarkers; D004268:DNA-Binding Proteins; C508609:IL10 protein, human; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; C490412:NR4A3 protein, human; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D016753:Interleukin-10; D015847:Interleukin-4; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9
Alternative macrophages; Atherosclerosis; Macrophage phenotypes; Nuclear receptors