1. The neuron-derived orphan receptor 1 (NOR1) is induced upon human alternative macrophage polarization and stimulates the expression of markers of the M2 phenotype
- Author
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Stéphan Haulon, Corinne Copin, Julie Dubois-Chevalier, Bart Staels, Christophe Zawadzki, Jérôme Eeckhoute, Giulia Chinetti-Gbaguidi, Sophie Colin, F. De Paoli, Christian Duhem, Jonathan Vanhoutte, Philippe Lefebvre, Brigitte Jude, and Bruno Derudas
- Subjects
Macrophage colony-stimulating factor ,Carotid Artery Diseases ,Receptors, Steroid ,Time Factors ,Nerve growth factor IB ,Macrophage-activating factor ,Primary Cell Culture ,Macrophage polarization ,Biology ,Transfection ,Animals ,Humans ,Gene Silencing ,Cells, Cultured ,Orphan receptor ,Receptors, Thyroid Hormone ,Macrophages ,Cell Differentiation ,Macrophage Activation ,Molecular biology ,Plaque, Atherosclerotic ,Neuron-derived orphan receptor 1 ,Cell biology ,Interleukin-10 ,DNA-Binding Proteins ,Mice, Inbred C57BL ,Interleukin 10 ,Interleukin 1 Receptor Antagonist Protein ,Phenotype ,Matrix Metalloproteinase 9 ,RNA Interference ,Interleukin-4 ,Cardiology and Cardiovascular Medicine ,STAT6 Transcription Factor ,Mannose receptor ,Biomarkers ,Signal Transduction - Abstract
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. Objectives To determine the expression and the functions of NOR1 in human alternative macrophages. Methods and 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.
- Published
- 2014