Nur77-deficiency in bone marrow-derived macrophages modulates inflammatory responses, extracellular matrix homeostasis, phagocytosis and tolerance

BMC Genomics

Research Article

Perry D. Moerland¹  Alex F. de Vos²  Goran Marinković³  Duco S. Koenis³  Claudia M. van Tiel³  Carlie J. M. de Vries³  Anouk A. J. Hamers⁴  Milka Sokolović⁵  Carmen Argmann⁶ 

[1] Bioinformatics Laboratory, Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;Present address: Department of Inflammation Biology, La Jolla Institute for Allergy and Immunology, San Diego, USA;Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;Present address: European Food Information Council, Brussels, Belgium;Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;Present address: Institute for Genomics and Multiscale Biology Mount Sinai Hospital, New York, USA;

关键词: Nur77;    TR3;    NR4A1;    Macrophage;    Collagen;    Inflammation;    SDF-1α;    Rac1;    CX3CR1;   

DOI  :  10.1186/s12864-016-2469-9

 received in 2015-04-24, accepted in 2016-02-12,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundThe 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.ResultsIn 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.ConclusionsAltogether these data identify Nur77 as a modulator of macrophage function and an interesting target to treat chronic inflammatory disease.

【 授权许可】

CC BY   
© Hamers et al. 2016