Transcriptome of cardiac tissue from WT mice, cardiac macrophages depleted mice, and mice deficient for Mertk and LxR
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA416139 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6231700.fastq.gz | Fastqsanger.gz | |||
| SRR6231691.fastq.gz | Fastqsanger.gz | |||
| SRR6231701.fastq.gz | Fastqsanger.gz | |||
| SRR6231692.fastq.gz | Fastqsanger.gz | |||
| SRR6231693.fastq.gz | Fastqsanger.gz |
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Project description:Our study aims to analyze the effect in whole cardiac transcriptome of cardiac macrophage depletion and the lack of receptors implicated in phagocytosis.
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Project description:Macrophages play a critical role in the pathogenesis and progression of heart failure, wherein sustained cardiomyocyte apoptosis is a key feature. The MER proto-oncogene tyrosine kinase (MERTK) is a critical receptor that mediates the efferocytosis of apoptotic cells by macrophages. However, the role and mechanism of action of MERTK in pressure overload-induced heart failure remains unclear. Here, we demonstrate that MERTK expression was upregulated in cardiac tissue macrophages of mice with pressure overload-induced heart failure. Deletion of MERTK ameliorated transverse aortic constriction (TAC)- and Ang II-induced cardiac hypertrophy and heart failure. This protective effect was associated with reduced type I interferon signaling and was reversed by interferon receptor activation. Efferocytosis assays were performed to demonstrate that mitochondrial double-stranded RNA from apoptotic cardiomyocytes activated Toll-like receptor 3 in macrophages, promoting Interferon beta (IFNb) expression. In vitro experiment identified that IFNb sensitized cardiomyocytes to Ang II stimulation by augmenting the P53 pathway, suppressing Ang II-induced protective mitophagy and promoting cardiomyocyte apoptosis. In conclusion, macrophage MERTK receptor exacerbated post-TAC heart failure and cardiac hypertrophy by mediating the phagocytosis of apoptotic cardiomyocytes and promoting IFNb expression. This study provides novel insights into the role of macrophage MERTK-mediated efferocytosis and type I interferon response in the pathogenesis of heart failure. These findings highlight an unrecognized function of MERTK in pressure overload-induced cardiac remodeling and identify IFNb as a key downstream effector of MERTK in this pathological process
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Project description:LXR is a transcription factor. Two isoforms exist in mice (alpha and beta). They are both expressed in the liver. We examined the role of LXR by obtaining gene expression profiles from the livers of wild-type and LXR-/- mice from the same genetic background. Liver gene expression was measured from male mice (5 mice/group) of genotypes wild-type and LXR-/- on a mixed Sv129/C57Bl6J background (Repa et al. , 2000, Science, 289(5484):1524-9; Cummins et al., 2006, J Clin Invest,116(7):1902-12) fed for 7 weeks a normal diet (ND) or a Western diet (WD).
2012-11-07 | E-GEOD-38083 | 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. 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.
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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.
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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 | GSE210548 | 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.
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Project description:Androgen deprivation in PTEN/LXR -/- mice
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Project description:LXR is a transcription factor. Two isoforms exist in mice (alpha and beta). They are both expressed in the liver. We examined the role of LXR by obtaining gene expression profiles from the livers of wild-type and LXR-/- mice from the same genetic background.
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Project description:Cardiac resident MerTK+ macrophages exert multiple protective roles post-ischemic injury, however, the mechanisms regulating their fate are not fully understood. Here we show that GAS6-inducible transcription factor ATF3 prevents apoptosis of MerTK+ macrophages after ischemia-reperfusion (IR) injury, by repressing the transcription of multiple genes involved in type I interferon expression (Ifih1 and Infb1) and apoptosis (Apaf1). Mice lacking ATF3 in cardiac macrophages or myeloid cells showed excessive loss of MerTK+ cardiac macrophages, poor angiogenesis, and worse heart dysfunction post-IR, which were rescued by the transfer of MerTK+ cardiac macrophages. GAS6 administration improved cardiac repair in an ATF3-dependent manner. Finally, we showed a negative association of GAS6 and ATF3 expression with the risk of major adverse cardiac events in patients with ischemic heart disease. These results indicate that the GAS6-ATF3 axis has a protective role against IR injury by regulating MerTK+ cardiac macrophage survival/proliferation.
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