Vitamin D regulates MerTK-dependent phagocytosis in human myeloid cells
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ABSTRACT:
PROVIDER: PRJNA626666 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11576249_1.fastq.gz | Fastqsanger.gz | |||
| SRR11576249_2.fastq.gz | Fastqsanger.gz | |||
| SRR11576250_1.fastq.gz | Fastqsanger.gz | |||
| SRR11576250_2.fastq.gz | Fastqsanger.gz | |||
| SRR11576251_1.fastq.gz | Fastqsanger.gz |
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Project description:Vitamin D deficiency is a major environmental risk factor for the development of multiple sclerosis (MS). The major circulating metabolite of vitamin D (25OHD) is converted to the active form (calcitriol) by the hydroxylase enzyme CYP27B1. In MS lesions the tyrosine kinase MerTK expressed by microglia and macrophages regulates phagocytosis of myelin debris and apoptotic cells that can accumulate and inhibit tissue repair and remyelination. We show that calcitriol downregulates MerTK mRNA and protein expression in primary adult human microglia and monocyte-derived macrophages, thereby inhibiting myelin phagocytosis and apoptotic cell clearance. Proinflammatory myeloid cells express high levels of CYP27B1 compared to homeostatic (TGFb-treated) myeloid cells. Only proinflammatory cells in the presence of TNF-a generate calcitriol from 25OHD, resulting in repression of MerTK expression and function. The selective production of calcitriol in proinflammatory myeloid cells leading to downregulation of MerTK-mediated phagocytosis has the potential to reduce the risk for auto-antigen presentation while retaining the phagocytic ability of homeostatic myeloid cells, thereby contributing to inflammation reduction and enhanced tissue repair.
2020-04-21 | GSE148986 | GEO
Project description:Early life stress such as childhood abues and childhood neglect has been frequently implicated in evoking mental disorders later in life. However, it is not well understood what is the underlying mechanism between early life stress and mental disorders. Our in vitro, in vivo and brain organoid experiments revealed that stress hormones increase Mertk expression in astrocytes through glucocorticoid receptor (GR). Furthermore, early life stress (ESD) exposure significantly incrased astrocyte-mediated synapse phagocytosis via GR/MERTK pathway in various brain regions including somatosensory cortex and orbitofrontal cortex. In those brain regions, the excitatory postsynaptic density was remarkably decreased with an increase in astrocytic phagocytosis of excitatory postsynapses. Importantly, ablating GR or MERTK in astrocytes prevented ESD-induced loss of excitatory snapses, abnormal neural activities and behavioral deficits. Taken together, this study revelas a new role of astrocytic GR/MERTK pathway in evoking stress-induced abnormal behaviors in mice, suggesting astrocytic GR/MERTK signaling could be a potential therapeutic target for stress-induced mental disorders.
2023-08-22 | GSE234945 | GEO
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:Knockout (KO) mouse models play critical roles in elucidating biological processes behind disease-associated or disease-resistant traits. As a consequence of gene KO, mice display certain phenotypes. Based on insight into the molecular role of said gene in a biological process, it is inferred that the particular biological process causally underlies the trait. This approach has been crucial towards understanding the basis of pathological and/or advantageous traits associated with Mertk KO. MERTK is a receptor tyrosine kinase with a critical role in phagocytosis of apoptotic cells or cellular debris. Therefore, early-onset, severe retinal degeneration was described to be a direct consequence of failed phagocytosis of photoreceptor outer segments by retinal pigment epithelia. Similarly, enhanced anti-tumor immunity was inferred to result from the failure of macrophages to dispose cancer cell corpses, resulting in a pro-inflammatory tumor microenvironment. Here we report that the loss of Mertk alone is not sufficient for retinal degeneration. This trait only manifests when the function of the paralog Tyro3 is concomitantly lost. Additionally, the dramatic resistance against two syngeneic mouse tumor models observed in Mertk KO cannot, at least entirely, be ascribed to the loss of Mertk. The widely used Mertk KO carries multiple coincidental changes in its genome that affect the expression of a number of genes, including Tyro3. Nonetheless, neither Tyro3, nor macrophage phagocytosis by alternate genetic redundancy, accounts for the absence of anti-tumor immunity in two independent Mertk KOs. Collectively, our results indicate that context-dependent epistasis of independent modifier alleles determine Mertk KO traits.
2022-08-26 | GSE205070 | GEO
Project description:Severe, early-onset photoreceptor (PR) degeneration associated with MERTK mutations is thought to result from failed phagocytosis by retinal pigment epithelium (RPE). Notwithstanding, the severity and onset of PR degeneration in mouse models of Mertk ablation is determined by the hypomorphic expression or the loss of the Mertk paralog Tyro3. Here we find that loss of Mertk and reduced expression/loss of Tyro3 led to RPE inflammation, even before eye-opening. Incipient RPE inflammation cascaded to involve microglia activation and PR degeneration with monocyte infiltration. Inhibition of RPE inflammation with the JAK1/2 inhibitor ruxolitinib mitigated PR degeneration in Mertk -/- mice. Neither inflammation nor severe, early-onset PR degeneration were observed in mice with defective phagocytosis alone. Thus, inflammation drives severe, early-onset PR degeneration-associated with Mertk loss of function.
2023-01-20 | GSE214005 | GEO
Project description:Vitamin B6 addiction in acute myeloid leukemia
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Project description:Whole transcriptome RNA-seq analysis to measure group-wise RNA expression level of the MERTK gene in 3 healthy controls (known to be homozygous non-risk haplotype at MERTK gene locus) and to compare this to the group-wise RNA expression level of the MERTK gene in 5 Multiple Sclerosis-affected (MS-affected) individuals (known to be homozygous for the MS risk haplotype at the MERTK gene locus). We sequenced the whole transcriptome of 3 healthy control samples which were all homozygous for the MS non-risk haplotype at the MERTK gene. We also did the same RNA-seq protocol on 5 MS-affected subjects that were all homozygous for the Risk haplotype at the MERTK gene. All 8 samples were sequenced evenly across 3 lanes of an Illumina HiSeq NGS machine to remove any batch-type effects that could be caused by sequencing e.g. all cases in one lane and all controls in another lane.
2016-02-06 | E-GEOD-77598 | biostudies-arrayexpress
Project description:The genomes of myeloid malignancies are characterized by epigenomic abnormalities. Heterozygous, inactivating TET2 mutations and neomorphic IDH mutations are recurrent and mutually exclusive in acute myeloid leukemia (AML) genomes. Ascorbic Acid (vitamin C) has been shown to stimulate the catalytic activity of TET2 in vitro and thus we sought to explore its effect in a leukemic model expressing IDH1R132H. Vitamin C treatment induced an IDH1R132H dependent reduction in cell proliferation and an increase in expression of genes involved in leukocyte differentiation. Vitamin C induced differentially methylated regions (DMRs) that displayed a significant overlap with enhancers implicated in myeloid differentiation and were enriched in sequence elements for the hematopoietic transcription factors RUNX1 and PU.1. ChIP-seq of PU.1 and RUNX1 revealed a significant loss of PU.1 and increase of RUNX1 bound DNA elements accompanied by their demethylation following vitamin C treatment. Additionally, vitamin C induced an increase in H3K27ac flanking sites bound by RUNX1. Based on these data we propose a model of vitamin C induced epigenetic remodelling of transcription factor binding sites driving differentiation in a leukemic model.
2017-07-01 | GSE87623 | GEO
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