Stress induces behavioral abnormalities by increasing expression of phagocytic receptor MERTK in astrocytes to promote synapse phagocytosis
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ABSTRACT:
PROVIDER: PRJNA983785 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24917613_1.fastq.gz | Fastqsanger.gz | |||
| SRR24917613_2.fastq.gz | Fastqsanger.gz | |||
| SRR24917614_1.fastq.gz | Fastqsanger.gz | |||
| SRR24917614_2.fastq.gz | Fastqsanger.gz | |||
| SRR24917615_1.fastq.gz | Fastqsanger.gz |
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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: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.
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Project description:The ability of Entamoeba histolytica to phagocytose host cells correlates to observed virulence in vivo. To better understand the mechanism of phagocytosis we used paramagnetic beads coated with host ligand and sorted trophozoites based on phagocytic ability. Gene expression was then measured in both the sorted phagocytic and non-phagocytic populations using a custom Affymetrix chip for E. histolytica. Feed forward regulation of phagocytosis by Entamoeba histolytica. Infection and Immunity. PMID 23045476 M280 Streptavidin Dynabeads (Invitrogen) were labeled with 20ug/mL biotinylated Human C1q (Quidel). Entamoeba histolytica (strain HM1) were washed twice with PBS then resuspended with the labeled beads at a 10:1 ratio of beads to trophozoites. Samples were incubated at 37°C for 45 minutes, washed twice with agitation to remove adherent beads, then resuspended in MACS buffer. Samples were loaded into magnetic columns (Miltenyi Biotec) and trophozoites were seperated according to manufacturer's protocols. phagocytic vs. non-phagocytic Entamoeba histolytica populations
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Project description:Vitamin D regulates MerTK-dependent phagocytosis in human myeloid cells
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Project description:During adult hippocampal neurogenesis, the majority of newborn cells undergo apoptosis and are rapidly phagocytosed by resident microglia in order to avoid disturbing the surrounding neurons. Here, we propose that phagocytosis is not merely a passive process of corpse removal but has an active role in maintaining adult hippocampal neurogenesis. First, we found that neurogenesis was disrupted in three defective microglial phagocytosis KO models in vivo (P2Y12, MerTK/Axl , GPR34). We then followed an in vitro approach to perform a transcriptomic analysis of microglial phagocytosis and identified genes involved in metabolism, chromatin remodeling, and neurogenesis-related functions. Finally, we determined that the phagocytic microglia secretome limits the production of new neurons both in vivo and in vitro. Our data suggest that reprogrammed phagocytic microglia acts as a sensor of local cell death, modulating the balance between cell proliferation and cell survival in the neurogenic niche, supporting the long-term maintenance of adult hippocampal neurogenesis.
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Project description:The ability of Entamoeba histolytica to phagocytose host cells correlates to observed virulence in vivo. To better understand the mechanism of phagocytosis we used paramagnetic beads coated with host ligand and sorted trophozoites based on phagocytic ability. Gene expression was then measured in both the sorted phagocytic and non-phagocytic populations using a custom Affymetrix chip for E. histolytica. Feed forward regulation of phagocytosis by Entamoeba histolytica. Infection and Immunity. PMID 23045476
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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.
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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.
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Project description:Targeting the reprogramming and phagocytic capacities of tumor-associated macrophages (TAMs) has emerged as a therapeutic opportunity for cancer treatment. Here, we demonstrate that leukemic cell phagocytosis triggers the proinflammatory activation of TAMs as demonstrated by the upregulation and dowregulation of, respectively, proinflammatory and anti-inflammatory genes in phagocytic macrophages (Phago+) with respect to non-phagocytic macrophages (Phago-).
2022-10-25 | E-MTAB-12280 | biostudies-arrayexpress
Project description:The Drosophila phagocytic receptor Eater is expressed specifically in phagocytic hemocytes. It contributes to host immune defense and is required for survival of bacterial infections. Eater is involved in recognition and phagocytosis of bacteria. We used microarrays to determine whether any gene expression changes after bacterial phagocytosis are dependent on the expression of the phagocytic scavenger receptor Eater. We found transcriptional regulation in response to bacterial internalization, but no significant differences between controls and samples in which eater expression had been diminshed by RNAi eater knock down. Drosophila S2 cells, a hemocyte-derived cell line with phagocytic properties, were exposed to a mixture of Gram-positive and Gram-negative bacteria at conditions of 50% of cell binding. At different time points of synchronized phagocytosis (30, 90 and 180 minutes) total RNA was extracted and subjected to microarray analysis. We compared S2 cells in which Eater expression was decreased by RNA interference with control S2 cells exposed to irrelevant double-stranded (pBR322). Three independent experiments were performed corresponding to three biological replicates. Decreased phagocytosis due to RNAi eater knock down was controlled in all cases.
2011-08-24 | E-GEOD-31564 | biostudies-arrayexpress