Expression data for various immune cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE89332 | GEO | 2016/12/31
SECONDARY ACCESSION(S): PRJNA352140
REPOSITORIES: GEO
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Project description:IkB proteins regulate the inhibition and activation of NF-kB transcription factor complexes. While classical IkB proteins keep NF-kB complexes inactive in the cytoplasm, atypical IkB proteins act on activated NF-kB complexes located in the nucleus. Most of the knowledge regarding the function of IkB proteins has been collected in vitro, while far less is known regarding their impact on activation and regulation of immune responses during in vivo infections. Combining in vivo Listeria monocytogenes (Lm) infection with comparative ex vivo transcriptional profiling of the hepatic response to the pathogen we observed that in contrast to wild type mice that mounted a robust inflammatory response, IkBNS-deficiency (Nfkbid gene) was generally associated with a transcriptional repression of innate immune responses. Whole tissue transcriptomics revealed a pronounced IkBNS-dependent reduction of myeloid cell-associated transcripts in the liver together with an exceptionally high Nfkbid promoter activity uncovered in Ly6C-high inflammatory monocytes prompted us to further characterized the specific contribution of IkBNS in the inflammatory response of monocytes to the infectious agent. Indeed, Ly6C-high monocytes primed during Lm infection in the absence of IkBNS displayed a blunted response compared to wild type-derived Ly6C-high monocytes as evidenced by the reduced early expression of hallmark transcripts of monocyte-driven inflammation such as Il-6, Nos2 and Il1-β. Strikingly, altered monocyte activation in IkBNS-deficient mice was associated with an exceptional resistance against Lm infection and protection was associated with a strong reduction in immunopathology in Lm target organs. Of note, mice lacking IkBNS exclusively in myeloid cells failed to resist Lm infection, indicating that the observed effect was not monocyte intrinsic but monocyte extrinsic. While serum cytokine-profiling did not discover obvious differences between wild type and IkBNS -/- mice for most of the analyzed mediators, IL-10 was virtually undetectable in IkBNS-deficient mice, both in the steady state and following Lm infection. Together, we show here a crucial role for IkBNS during Lm infection with IkBNS-deficient mice showing an overall blunted pro-inflammatory immune response attributed to a reduced pro-inflammatory signature in Ly6C-high monocytes. Reduced immunopathology and complete protection of mice against an otherwise lethal Lm infection identified IkBNS as molecular driver of inflammation in listeriosis.
2022-12-11 | GSE220265 | GEO
Project description:The pathways by which oncogenes, such as MLL-AF9, initiate transformation and leukemia in humans and mice are incompletely defined. In a study of target cells and oncogene dosage, we found that Mll-AF9, when under endogenous regulatory control, efficiently transformed LSK (Lin- Sca1+ c-kit+) stem cells while committed granulocyte-monocyte progenitors (GMPs) were transformation-resistant and did not cause leukemia. Mll-AF9 was expressed at higher levels in hematopoietic stem (HSC) than GMP cells. Mll- AF9 gene dosage effects were directly shown in experiments where GMPs were efficiently transformed by the high dosage of Mll-AF9 resulting from retroviral transduction. Mll-AF9 up-regulated expression of 196 genes in both LSK and progenitor cells, but to higher levels in LSKs than in committed myeloid progenitors. Keywords: mutant hematopoietic cells
2008-02-25 | GSE10627 | GEO
Project description:IkB proteins regulate the inhibition and activation of NF-kB transcription factor complexes. While classical IkB proteins keep NF-kB complexes inactive in the cytoplasm, atypical IkB proteins act on activated NF-kB complexes located in the nucleus. Most of the knowledge regarding the function of IkB proteins has been collected in vitro, while far less is known regarding their impact on activation and regulation of immune responses during in vivo infections. Combining in vivo Listeria monocytogenes (Lm) infection with comparative ex vivo transcriptional profiling of the hepatic response to the pathogen we observed that in contrast to wild type mice that mounted a robust inflammatory response, IkBNS-deficiency was generally associated with a transcriptional repression of innate immune responses. Whole tissue transcriptomics revealed a pronounced IkBNS-dependent (Nfkbid gene) reduction of myeloid cell-associated transcripts in the liver together with an exceptionally high Nfkbid promoter activity uncovered in Ly6C-high inflammatory monocytes prompted us to further characterized the specific contribution of IkBNS in the inflammatory response of monocytes to the infectious agent. Indeed, Ly6C-high monocytes primed during Lm infection in the absence of IkBNS displayed a blunted response compared to wild type-derived Ly6C-high monocytes as evidenced by the reduced early expression of hallmark transcripts of monocyte-driven inflammation such as Il-6, Nos2 and Il1-β. Strikingly, altered monocyte activation in IkBNS-deficient mice was associated with an exceptional resistance against Lm infection and protection was associated with a strong reduction in immunopathology in Lm target organs. Of note, mice lacking IkBNS exclusively in myeloid cells failed to resist Lm infection, indicating that the observed effect was not monocyte intrinsic but monocyte extrinsic. While serum cytokine-profiling did not discover obvious differences between wild type and IkBNS -/- mice for most of the analyzed mediators, IL-10 was virtually undetectable in IkBNS-deficient mice, both in the steady state and following Lm infection. Together, we show here a crucial role for IkBNS during Lm infection with IkBNS-deficient mice showing an overall blunted pro-inflammatory immune response attributed to a reduced pro-inflammatory signature in Ly6C-high monocytes. Reduced immunopathology and complete protection of mice against an otherwise lethal Lm infection identified IkBNS as molecular driver of inflammation in listeriosis.
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Project description:The heterogeneity of epithelial-to-mesenchymal transition (EMT) programs is manifest in the diverse EMT-like phenotypes occurring during tumor progression. However, little is known about the mechanistic basis and functional role of specific forms of EMT in cancer. Here we address this question in lung adenocarcinoma (LUAD) cells that enter a dormancy period in response to TGF-β upon disseminating to distant sites. LUAD cells with the capacity to enter dormancy are characterized by expression of SOX2 and NKX2-1 primitive progenitor markers. In these cells, TGF-β induces growth inhibition accompanied by a full EMT response that subsequently transitions into an atypical mesenchymal state of round morphology and lacking actin stress fibers. TGF-β induces this transition by driving the expression of the actin-depolymerizing factor gelsolin, which changes a migratory, stress fiber-rich mesenchymal phenotype into a cortical actin-rich, spheroidal state. This transition lowers the biomechanical stiffness of metastatic progenitors, protecting them from killing by mechanosensitive cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. Inhibiting this actin depolymerization process clears tissues of dormant metastatic cells. Thus, LUAD primitive progenitors undergo an atypical EMT as part of a strategy to evade immune-mediated elimination during dormancy. Our results provide a mechanistic basis and functional role of this atypical EMT response of LUAD metastatic progenitors and further illuminate the role of TGF-β as a crucial driver of immune evasive metastatic dormancy.
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Project description:Cancer cells disseminated to distant sites enter a period of dormancy before generating overt metastases. The ability of these cells to elude immune surveillance determines their persistence as latent disease. We report that TGF-β promotes dormancy in lung adenocarcinoma (LUAD) mouse models by placing disseminated SOX2+ and NKX2-1+ progenitors in a quiescent state that biomechanically averts killing by cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. In these primitive progenitors, TGF-β induces an atypical epithelial-to-mesenchymal transition (EMT) lacking actin stress fibers. TGF-β drives expression of the actin-depolymerizing factor gelsolin that changes a migratory, stress fiber-rich mesenchymal phenotype into a cortical actin-rich, spheroidal state. This transition lowers the stiffness of metastatic progenitors and their killing by mechanosensitive CTLs and NK cells. Thus, LUAD primitive progenitors activate a biomechanical process to evade immune-mediated elimination during prolonged dormancy periods. Inhibiting this process clears tissues of dormant metastatic cells.
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