Abstract
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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-2469-9) contains supplementary material, which is available to authorized users.
Highlights
The nuclear orphan receptor Nur77 (NR4A1, TR3, or NGFI-B) has been shown to modulate the inflammatory response of macrophages
Expression profiling reveals that Nur77 modulates inflammatory gene expression in macrophages To understand the function of Nur77 in macrophages, RNA was isolated from bone marrow-derived macrophages (BMM) isolates derived from Nur77-KO and WT mice and transcriptionally profiled
In these cells 324 genes were differentially expressed in Nur77-KO compared with WT BMM (p-value
Summary
The nuclear orphan receptor Nur (NR4A1, TR3, or NGFI-B) has been shown to modulate the inflammatory response of macrophages. Nuclear receptor Nur, known as NR4A1, TR3 or NGFI-B, is a member of the NR4A receptor subfamily that comprises Nurr (NR4A2, NOT) and NOR-1 (NR4A3, MINOR). The NR4As consist of an N-terminal transactivation domain, a central zinc finger DNA binding domain Nur can bind as a monomer to the so-called NGFI-B response element (NBRE; AAAGGCTA) in the promoter region of direct target genes. Nur and Nurr can form homodimers and heterodimers with retinoid X receptor and bind a DR-5 response element [4]. Gene transcription is modulated by Nur itself through transrepression of other transcription factors. Nur exhibits a direct, inhibitory interaction with the p65 subunit of NFκB [5, 6]
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