Regulation of Macrophage IFNγ-Stimulated Gene Expression by the 1 Transcriptional Coregulator CITED1 - KnockOut
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ABSTRACT:
PROVIDER: PRJNA903206 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22341537_1.fastq.gz | Fastqsanger.gz | |||
| SRR22341537_2.fastq.gz | Fastqsanger.gz | |||
| SRR22341538_1.fastq.gz | Fastqsanger.gz | |||
| SRR22341538_2.fastq.gz | Fastqsanger.gz | |||
| SRR22341539_1.fastq.gz | Fastqsanger.gz |
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Similar Datasets
Project description:Macrophages are highly dynamic innate immune cells that adopt temporary phenotypes, known as polarization states, in response to changing environmental signals to combat microbial infection and contribute to the maintenance of tissue homeostasis. During the early stages of an infection, exposure to interferon-gamma (IFNγ) and microbial ligands induce M1 polarization, a heightened proinflammatory anti-microbial state, by regulating the expression of interferon stimulated genes (ISGs). While this response must be sufficiently vigorous to ensure the successful clearance of invading pathogens, it must also be spatially and temporally restricted to prevent uncontrolled inflammation that could result in tissue damage and disease. This is controlled by a variety of cell-extrinsic and -intrinsic mechanisms, including the expression of CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxyl-terminal domain 2 (CITED2), a transcriptional coregulator that limits IFNγ-stimulated proinflammatory gene expression by inhibiting STAT1- and IRF1-regulated ISGs. In this study, we show that CITED1, another member of the CITED family of proteins, is itself an ISG and is expressed in a STAT1-dependent manner, and that IFNγ stimulates the nuclear accumulation of fluorescently tagged CITED1 proteins. In contrast to CITED2, ectopic expression of CITED1 enhanced the expression of a subset of ISGs, including Ccl2, Ifit3b, Isg15, and Oas2. This effect was reversed in a Cited1 null cell line produced by CRISPR-based genomic editing. Collectively, these data show that CITED1 helps to maintain proinflammatory gene expression during periods of prolonged IFNγ exposure and suggests a distinct and antagonistic relationship between CITED proteins in the regulation of macrophage inflammatory function.
2023-01-01 | GSE218356 | GEO
Project description:Macrophages are highly dynamic innate immune cells that adopt temporary phenotypes, known as polarization states, in response to changing environmental signals to combat microbial infection and contribute to the maintenance of tissue homeostasis. During the early stages of an infection, exposure to interferon-gamma (IFNγ) and microbial ligands induce M1 polarization, a heightened proinflammatory anti-microbial state, by regulating the expression of interferon stimulated genes (ISGs). While this response must be sufficiently vigorous to ensure the successful clearance of invading pathogens, it must also be spatially and temporally restricted to prevent uncontrolled inflammation that could result in tissue damage and disease. This is controlled by a variety of cell-extrinsic and -intrinsic mechanisms, including the expression of CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxyl-terminal domain 2 (CITED2), a transcriptional coregulator that limits IFNγ-stimulated proinflammatory gene expression by inhibiting STAT1- and IRF1-regulated ISGs. In this study, we show that CITED1, another member of the CITED family of proteins, is itself an ISG and is expressed in a STAT1-dependent manner, and that IFNγ stimulates the nuclear accumulation of fluorescently tagged CITED1 proteins. In contrast to CITED2, ectopic expression of CITED1 enhanced the expression of a subset of ISGs, including Ccl2, Ifit3b, Isg15, and Oas2. This effect was reversed in a Cited1 null cell line produced by CRISPR-based genomic editing. Collectively, these data show that CITED1 helps to maintain proinflammatory gene expression during periods of prolonged IFNγ exposure and suggests a distinct and antagonistic relationship between CITED proteins in the regulation of macrophage inflammatory function.
2023-01-01 | GSE217961 | GEO
Project description:Regulation of Macrophage IFNγ-Stimulated Gene Expression by the 1 Transcriptional Coregulator CITED1
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Project description:Macrophages serve as a first line of defense against microbial pathogens. Exposure to interferon-γ (IFNγ) increases interferon-stimulated gene (ISG) expression in these cells, resulting in enhanced antimicrobial and proinflammatory activity. Although this response must be sufficiently vigorous to ensure the successful clearance of pathogens, it must also be carefully regulated to prevent tissue damage. This is controlled in part by CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxyl-terminal domain 2 (CITED2), a transcriptional coregulator that limits ISG expression by inhibiting STAT1 and IRF1. Here, we show that the closely related Cited1 is an ISG, which is expressed in a STAT1-dependent manner, and that IFNγ stimulates the nuclear accumulation of CITED1 protein. In contrast to CITED2, ectopic CITED1 enhanced the expression of a subset of ISGs, including Ccl2, Ifit3b, Isg15 and Oas2. This effect was reversed in a Cited1-null cell line produced by CRISPR-based genomic editing. Collectively, these data show that CITED1 maintains proinflammatory gene expression during periods of prolonged IFNγ exposure and suggest that there is an antagonistic relationship between CITED proteins in the regulation of macrophage inflammatory function. This article has an associated First Person interview with the first author of the paper.
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Project description:Ocular immune privilege (IP) limits immune surveillance of intraocular tumors as certain immunogenic tumor cell lines (P815, E.G7-OVA) that are rejected when transplanted in the skin grow progressively when placed in the anterior chamber (a.c.) of the eye. As splenectomy (SPLNX) is known to terminate ocular IP, we characterized immune mechanisms responsible for spontaneous rejection of intraocular tumors in SPLNX mice as a first step toward identifying how to restore tumoricidal activity within the eye. Microarray data showed a 3-fold increase in interferon (IFN)-γ and a 2.7-fold increase in Fas ligand (FasL). There was a robust increase in transcripts (127 of 408 surveyed) from interferon (IFN)-stimulated genes and a marked decrease (in 40 of 192 surveyed) in the expression of cell-cycle-associated genes. Non-microarray data confirmed that IFNγ, FasL and CD8+ T cells but not perforin or TNFα were required for elimination of intraocular E.G7-OVA tumors that culminated in destruction of the eye (ocular phthsis). IFNγ and FasL did not target tumor cells directly as the majority of SPLNX IFNγR1-/- mice and Fas-defective lpr mice failed to eliminate ocular E.G7-OVA tumors that expressed Fas and IFNγR1. Bone marrow chimeras showed that immune cell expression of IFNγR1 and Fas was critical and that SPLNX increased the frequency of activated macrophages within ocular tumors in an IFNγ- and Fas/FasL-dependent manner. Rejection of intraocular tumors was associated with increased ocular mRNA expression of several inflammatory genes including FasL, NOS2, CXCL2 and T-bet. Our data support a model in which IFNγ- and Fas/FasL-dependent activation of intratumoral macrophage by CD8+ T cells promotes severe intraocular inflammation that indirectly eliminates intraocular tumors by inducing phthisis. The immunosuppressive mechanisms which maintain ocular IP likely interfere with the interaction between CD8+ T cells and macrophage to limit immunosurveillance of intraocular tumors. C57BL/6 mice that were splenectomized (Tumor_splnx) or were not surgically manipulated (Tumor_intact) were challenged with 10^4 luciferase-expressing E.G7-OVA cells injected into the anterior chamber of the eye. Fifteen days later, the animals were euthanized and tumor-bearing eyes were removed.
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