Host responses to S. pneumoniae in wild type and Mertk mutant mice II
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ABSTRACT:
PROVIDER: PRJNA866140 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR20829124_1.fastq.gz | Fastqsanger.gz | |||
| SRR20829124_2.fastq.gz | Fastqsanger.gz | |||
| SRR20829125_1.fastq.gz | Fastqsanger.gz | |||
| SRR20829125_2.fastq.gz | Fastqsanger.gz | |||
| SRR20829126_1.fastq.gz | Fastqsanger.gz |
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Project description:Streptococcus pneumoniae is the leading cause of community-acquired pneumonia. Mertk is an efferocytosis receptor involved in the recognition and removal of apoptotic debris by macrophages and other phagocytic cells. Here we show that Mertk negatively regulates the clearance of S. pneumoniae, as measured by the greater number of viable bacteria in the lung of wild type vs. Mertk-/- mice 24 hours post-inoculation. The impaired clearance observed in wild type mice was associated with a greater number of neutrophils in the bronchoalveolar lavage (BAL) and lower concentration of IFNγ in the BAL fluid; however, similar enhancement of clearance was observed in Mertk-/- mice receiving neutralizing IFNγ antibody. Mertk is highly expressed on alveolar macrophages. Transcriptomic changes observed in primary Mertk-/- alveolar macrophages were associated with leukocyte activation, cellular motility, and response to stimulus. Mertk deficiency similarly enhanced proinflammatory gene expression in S. pneumoniae-stimulated alveolar macrophages in vitro and in pneumonic lung tissue. Thus, Mertk contributes to alveolar macrophage homeostasis through the receptor’s immunomodulatory role. Naive Mertk-/- alveolar macrophages appear primed for an inflammatory response to S. pneumoniae leading to greater cell motility, improved bacterial killing and enhancement of other innate immune cells through the production of inflammatory mediators.
2025-03-04 | GSE210549 | GEO
Project description:Streptococcus pneumoniae is the leading cause of community-acquired pneumonia. Mertk is an efferocytosis receptor involved in the recognition and removal of apoptotic debris by macrophages and other phagocytic cells. Here we show that Mertk negatively regulates the clearance of S. pneumoniae, as measured by the greater number of viable bacteria in the lung of wild type vs. Mertk-/- mice 24 hours post-inoculation. The impaired clearance observed in wild type mice was associated with a greater number of neutrophils in the bronchoalveolar lavage (BAL) and lower concentration of IFNγ in the BAL fluid; however, similar enhancement of clearance was observed in Mertk-/- mice receiving neutralizing IFNγ antibody. Mertk is highly expressed on alveolar macrophages. Transcriptomic changes observed in primary Mertk-/- alveolar macrophages were associated with leukocyte activation, cellular motility, and response to stimulus. Mertk deficiency similarly enhanced proinflammatory gene expression in S. pneumoniae-stimulated alveolar macrophages in vitro and in pneumonic lung tissue. Thus, Mertk contributes to alveolar macrophage homeostasis through the receptor’s immunomodulatory role. Naive Mertk-/- alveolar macrophages appear primed for an inflammatory response to S. pneumoniae leading to greater cell motility, improved bacterial killing and enhancement of other innate immune cells through the production of inflammatory mediators.
2025-03-04 | GSE210550 | GEO
Project description:Streptococcus pneumoniae is the leading cause of community-acquired pneumonia. Mertk is an efferocytosis receptor involved in the recognition and removal of apoptotic debris by macrophages and other phagocytic cells. Here we show that Mertk negatively regulates the clearance of S. pneumoniae, as measured by the greater number of viable bacteria in the lung of wild type vs. Mertk-/- mice 24 hours post-inoculation. The impaired clearance observed in wild type mice was associated with a greater number of neutrophils in the bronchoalveolar lavage (BAL) and lower concentration of IFNγ in the BAL fluid; however, similar enhancement of clearance was observed in Mertk-/- mice receiving neutralizing IFNγ antibody. Mertk is highly expressed on alveolar macrophages. Transcriptomic changes observed in primary Mertk-/- alveolar macrophages were associated with leukocyte activation, cellular motility, and response to stimulus. Mertk deficiency similarly enhanced proinflammatory gene expression in S. pneumoniae-stimulated alveolar macrophages in vitro and in pneumonic lung tissue. Thus, Mertk contributes to alveolar macrophage homeostasis through the receptor’s immunomodulatory role. Naive Mertk-/- alveolar macrophages appear primed for an inflammatory response to S. pneumoniae leading to greater cell motility, improved bacterial killing and enhancement of other innate immune cells through the production of inflammatory mediators.
2025-03-04 | GSE210548 | GEO
Project description:Host responses to S. pneumoniae in wild type and Mertk mutant mice XT
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Project description:Host responses to S. pneumoniae in wild type and Mertk mutant mice I
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Project description:Host responses to S. pneumoniae in wild type and Mertk mutant mice III
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Project description:Tolerogenic dendritic cells (tol-DCs) offer a promising therapeutic potential for autoimmune diseases. Tol-DCs have been reported to inhibit immunogenic responses, yet little is known about the mechanisms controlling their tolerogenic status, as well as associated specific markers. Here we show that the anti-inflammatory TAM receptor tyrosine kinase MERTK, is highly expressed on clinical grade dexamethasone-induced human tol-DCs and mediates their tolerogenic effect. Neutralization of MERTK in allogenic mixed lymphocyte reactions as well as autologous DC-T cell cultures leads to increased T cell proliferation and IFN-g production. Additionally, we identify a previously unrecognized non-cell autonomous regulatory function of MERTK expressed on DCs. Recombinant Mer-Fc protein, used to mimic MERTK on DCs, suppresses naïve and antigen-specific memory T cell activation. This mechanism is mediated by the neutralization of the MERTK agonist Protein S (PROS1) expressed by T cells. We find that MERTK and PROS1 are expressed in human T cells upon TCR activation and drive an autocrine pro-proliferative mechanism. Collectively, these results suggest that MERTK on tol-DCs directly inhibits T cell activation through the competition for PROS1 interaction with MERTK in the T cells. Targeting MERTK may provide an interesting approach to effectively increase or suppress tolerance for the purpose of immunotherapy. The complete database comprised the expression measurements of 54,675 genes for: immature (n=9), mature (n=7) and tolerogenic (n=8). Influence of treatment with dexamethasone (n=3) and LPS (n=2) are included.
2015-01-29 | E-GEOD-56017 | biostudies-arrayexpress
Project description:Tolerogenic dendritic cells (tol-DCs) offer a promising therapeutic potential for autoimmune diseases. Tol-DCs have been reported to inhibit immunogenic responses, yet little is known about the mechanisms controlling their tolerogenic status, as well as associated specific markers. Here we show that the anti-inflammatory TAM receptor tyrosine kinase MERTK, is highly expressed on clinical grade dexamethasone-induced human tol-DCs and mediates their tolerogenic effect. Neutralization of MERTK in allogenic mixed lymphocyte reactions as well as autologous DC-T cell cultures leads to increased T cell proliferation and IFN-g production. Additionally, we identify a previously unrecognized non-cell autonomous regulatory function of MERTK expressed on DCs. Recombinant Mer-Fc protein, used to mimic MERTK on DCs, suppresses naïve and antigen-specific memory T cell activation. This mechanism is mediated by the neutralization of the MERTK agonist Protein S (PROS1) expressed by T cells. We find that MERTK and PROS1 are expressed in human T cells upon TCR activation and drive an autocrine pro-proliferative mechanism. Collectively, these results suggest that MERTK on tol-DCs directly inhibits T cell activation through the competition for PROS1 interaction with MERTK in the T cells. Targeting MERTK may provide an interesting approach to effectively increase or suppress tolerance for the purpose of immunotherapy.
2015-01-29 | GSE56017 | GEO
Project description:Fibrosis is a core pathway that drives the progression of multiple chronic diseases for which there is a paucity of safe and effective treatments. In these diseases, transforming growth factor–β (TGF-β)–driven scarring propels disease progression. However, targeting this ubiquitously expressed cytokine is unlikely to yield a viable and safe antifibrotic therapy; thus, identification of alternative mechanisms to inhibit TGF-β signalling is required. We identified Mer tyrosine kinase (MERTK) as a TGF-β–inducible nodal effector of fibrosis that is up-regulated with fibrosis in multiple organs in both mice and humans. MERTK also induces TGF-β expression and promotes it’s signalling resulting in a positive feedback loop that promotes fibrosis. Mechanistically, MERTK regulates both canonical and non-canonical TGFβ signalling. Further downstream, MERTK modulates the fibrotic regulatory gene transcription network by regulating chromatin accessibility, RNA polymerase II (pol II) pausing and reprograming the enhancer landscape. Using mouse models of kidney, lung, and liver fibrosis, we demonstrate that this fibrosis-promoting signalling loop can be interrupted by loss of MERTK expression, leading to marked attenuation of fibrosis. Pharmacologic MERTK inhibition reduced fibrosis either when initiated immediately after injury or when initiated after fibrosis is established. Together, this data suggests that MERTK plays a critical role in modulating organ fibrosis, while small-molecule MERTK inhibitors are an attractive target for the treatment of diseases characterized by fibrosis.
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Project description:Fibrosis is a core pathway that drives the progression of multiple chronic diseases for which there is a paucity of safe and effective treatments. In these diseases, transforming growth factor–β (TGF-β)–driven scarring propels disease progression. However, targeting this ubiquitously expressed cytokine is unlikely to yield a viable and safe antifibrotic therapy; thus, identification of alternative mechanisms to inhibit TGF-β signalling is required. We identified Mer tyrosine kinase (MERTK) as a TGF-β–inducible nodal effector of fibrosis that is up-regulated with fibrosis in multiple organs in both mice and humans. MERTK also induces TGF-β expression and promotes it’s signalling resulting in a positive feedback loop that promotes fibrosis. Mechanistically, MERTK regulates both canonical and non-canonical TGFβ signalling. Further downstream, MERTK modulates the fibrotic regulatory gene transcription network by regulating chromatin accessibility, RNA polymerase II (pol II) pausing and reprograming the enhancer landscape. Using mouse models of kidney, lung, and liver fibrosis, we demonstrate that this fibrosis-promoting signalling loop can be interrupted by loss of MERTK expression, leading to marked attenuation of fibrosis. Pharmacologic MERTK inhibition reduced fibrosis either when initiated immediately after injury or when initiated after fibrosis is established. Together, this data suggests that MERTK plays a critical role in modulating organ fibrosis, while small-molecule MERTK inhibitors are an attractive target for the treatment of diseases characterized by fibrosis.
2024-03-05 | GSE235612 | GEO