title: Nur77-deficiency in bone marrow-derived macrophages modulates inflammatory responses, extracellular matrix homeostasis, phagocytosis and tolerance.
abstract: BACKGROUND
  The nuclear orphan receptor Nur77 (NR4A1, TR3, or NGFI-B) has been shown to modulate the inflammatory response of macrophages. To further elucidate the role of Nur77 in macrophage physiology, we compared the transcriptome of bone marrow-derived macrophages (BMM) from wild-type (WT) and Nur77-knockout (KO) mice.
  
  
  RESULTS
  In line with previous observations, SDF-1α (CXCL12) was among the most upregulated genes in Nur77-deficient BMM and we demonstrated that Nur77 binds directly to the SDF-1α promoter, resulting in inhibition of SDF-1α expression. The cytokine receptor CX3CR1 was strongly downregulated in Nur77-KO BMM, implying involvement of Nur77 in macrophage tolerance. Ingenuity pathway analyses (IPA) to identify canonical pathways regulation and gene set enrichment analyses (GSEA) revealed a potential role for Nur77 in extracellular matrix homeostasis. Nur77-deficiency increased the collagen content of macrophage extracellular matrix through enhanced expression of several collagen subtypes and diminished matrix metalloproteinase (MMP)-9 activity. IPA upstream regulator analyses discerned the small GTPase Rac1 as a novel regulator of Nur77-mediated gene expression. We identified an inhibitory feedback loop with increased Rac1 activity in Nur77-KO BMM, which may explain the augmented phagocytic activity of these cells. Finally, we predict multiple chronic inflammatory diseases to be influenced by macrophage Nur77 expression. GSEA and IPA associated Nur77 to osteoarthritis, chronic obstructive pulmonary disease, rheumatoid arthritis, psoriasis, and allergic airway inflammatory diseases.
  
  
  CONCLUSIONS
  Altogether these data identify Nur77 as a modulator of macrophage function and an interesting target to treat chronic inflammatory disease.
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. a.a.hamers@amc.uva.nl.|Present address: Department of Inflammation Biology, La Jolla Institute for Allergy and Immunology, San Diego, USA. a.a.hamers@amc.uva.nl.
authors.forename: Anouk A J
authors.initials: AA
authors.lastname: Hamers
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. carmen.argmann@mssm.edu.|Present address: Institute for Genomics and Multiscale Biology Mount Sinai Hospital, New York, USA. carmen.argmann@mssm.edu.
authors.forename: Carmen
authors.initials: C
authors.lastname: Argmann
authors.affiliation: Bioinformatics Laboratory, Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. p.d.moerland@amc.uva.nl.
authors.forename: Perry D
authors.initials: PD
authors.lastname: Moerland
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. d.s.koenis@amc.uva.nl.
authors.forename: Duco S
authors.initials: DS
authors.lastname: Koenis
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. g.marinkovic@amc.uva.nl.
authors.forename: Goran
authors.initials: G
authors.lastname: Marinković
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. milkasokolovic@gmail.com.|Present address: European Food Information Council, Brussels, Belgium. milkasokolovic@gmail.com.
authors.forename: Milka
authors.initials: M
authors.lastname: Sokolović
authors.affiliation: Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. a.f.devos@amc.uva.nl.
authors.forename: Alex F
authors.initials: AF
authors.lastname: de Vos
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. c.j.devries@amc.uva.nl.
authors.forename: Carlie J M
authors.initials: CJ
authors.lastname: de Vries
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. c.m.vantiel@amc.uva.nl.
authors.forename: Claudia M
authors.initials: CM
authors.lastname: van Tiel
mesh_terms: D000818:Animals; D000073883:CX3C Chemokine Receptor 1; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism*; D005786:Gene Expression Regulation; D006706:Homeostasis; D007108:Immune Tolerance; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics / Q000378:metabolism*; D010587:Phagocytosis; D011401:Promoter Regions, Genetic; D000067996:RAW 264.7 Cells; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D000073883:CX3C Chemokine Receptor 1; D054377:Chemokine CXCL12; C471885:Cx3cr1 protein, mouse; C515256:Cxcl12 protein, mouse; D016328:NF-kappa B; D009479:Neuropeptides; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; C484602:Rac1 protein, mouse; D019707:Receptors, Chemokine; D003094:Collagen; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D020830:rac1 GTP-Binding Protein