Nur77-deficiency in bone marrow-derived macrophages modulates inflammatory responses, extracellular matrix
Anouk A J Hamers1,2, Carmen Argmann3,4, Perry D Moerland5
1Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. a.a.hamers@amc.uva.nl.
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.
Insights
The nuclear orphan receptor Nur77 regulates macrophage function by controlling inflammatory genes like SDF-1α and impacting extracellular matrix. Nur77 deficiency promotes chronic inflammatory diseases, suggesting it
Area of Science:
- Immunology and Molecular Biology: Focuses on macrophage function and inflammatory pathways.
Background:
- The nuclear orphan receptor Nur77 (NR4A1) modulates macrophage inflammatory responses.
- Investigated the role of Nur77 in macrophage physiology using gene expression analysis.
Purpose of the Study:
- To compare the transcriptome of wild-type (WT) and Nur77-knockout (KO) bone marrow-derived macrophages (BMM).
- To elucidate the specific mechanisms by which Nur77 influences macrophage function and extracellular matrix homeostasis.
Main Methods:
- Transcriptome comparison between WT and Nur77-KO BMM.
- Analysis of gene expression, including SDF-1α (CXCL12) and CX3CR1.
- Utilized Ingenuity Pathway Analysis (IPA) and Gene Set Enrichment Analysis (GSEA).
Main Results:
- Nur77 directly inhibits SDF-1α expression.
- Nur77 deficiency alters extracellular matrix homeostasis, increasing collagen and decreasing MMP-9 activity.
- Identified Rac1 as a novel regulator of Nur77-mediated gene expression, potentially enhancing phagocytosis in Nur77-KO BMM.
Conclusions:
- Nur77 modulates macrophage function, including inflammatory gene expression and extracellular matrix remodeling.
- Nur77 plays a role in preventing chronic inflammatory diseases such as osteoarthritis and rheumatoid arthritis.
- Nur77 represents a potential therapeutic target for chronic inflammatory conditions.
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