Inflammatory reactions and severe neutropenia in mice lacking the transcriptional repressor Gfi1
Abstract
The transcriptional repressor Gfi1 is a nuclear zinc-finger protein expressed in T-cell precursors in the thymus and in activated mature T lymphocytes. Previous experiments have shown that Gfi1 is involved in T-cell lymphomagenesis and in the development of T-cell progenitors. Here we show that Gfi1 is also expressed outside the lymphoid system in granulocytes and activated macrophages, cells that mediate innate immunity (that is, non-specific immunity). We have generated Gfi1-deficient mice (Gfi1-/-) and show that these animals are severely neutropenic and accumulate immature monocytic cells in blood and bone marrow. Their myeloid precursor cells are unable to differentiate into granulocytes upon stimulation with granulocyte colony-stimulating factor (G-CSF) but can develop into mature macrophages. We found that Gfi1-/- macrophages produce enhanced levels of inflammatory cytokines, such as tumor necrosis factor (TNF), interleukin-10 (IL-10) and IL-1beta, when stimulated with bacterial lipopolysaccharide (LPS) and that Gfi1-/- mice succumb to low doses of this endotoxin that are tolerated by wildtype mice. We conclude that Gfi1 influences the differentiation of myeloid precursors into granulocytes or monocytes and acts in limiting the inflammatory immune response.
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Two GMP regulatory states were demarcated by transcription factors involved in granulocyte (Cebpe, Gfi1) or monocyte (Irf8, Klf4) specification.
“Two were demarcated by TFs involved in granulocyte (e.g., Cebpe, Gfi1) or monocyte (e.g., Irf8, Klf4) specification10–12,22.”
From Single-cell analysis of mixed-lineage states leading to a binary cell fate choice (2016) · cites this paper as [11]
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Self-citation
- Authors
- Karsunky, H., Zeng, H., Schmidt, T., Zevnik, B., Kluge, R., Schmid, K. W., Dührsen, U., & Möröy, T.
- Affiliations
- Essen University Hospital (DE)
- Archdiocese of Cologne (DE)
- RWTH Aachen University (DE)
- Corresponding author
- Möröy, Tarik
- Venue
- Nature Genetics
- Published
- 2002-01-28
- Volume
- 30
- Issue
- 3
- Pages
- 295-300
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W2019670746
- Cited by
- 315
- References
- 12
- Citations by year
- 2026: 7 · 2025: 5 · 2024: 1 · 2023: 5 · 2022: 7 · 2021: 12 · 2020: 10 · 2019: 18 · 2018: 13 · 2017: 13 · 2016: 18 · 2015: 9 · 2014: 11 · 2013: 18 · 2012: 23
- FWCI
- 6.89
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- RWTH Publications (RWTH Aachen) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Blood disorders and treatments
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- GFI1, transcriptional repressor, zinc finger proteins, neutropenia, inflammatory cytokines, macrophages, granulocytes, myeloid differentiation, granulocyte colony-stimulating factor, lipopolysaccharide, endotoxemia, innate immunity, T cell development, TNF-α, IL-10, IL-1β
- MeSH terms
- Animals, Bone Marrow Cells, Cell Differentiation, DNA-Binding Proteins, Macrophages, Mice, Inbred C57BL, Repressor Proteins, Transcription Factors, Transcription, Genetic, Cytokines, Inflammation Mediators, Cell Lineage, Mice
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