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Neuronal CD47 Induces Microglial Phagocytosis Defects and Autism-like Behaviors While Mitigating Aβ-Induced Synaptic Loss

ABSTRACT: Neuronal CD47 Induces Microglial Phagocytosis Defects and Autism-like Behaviors While Mitigating Aβ-Induced Synaptic Loss

PROVIDER: PRJNA1097467 | ENA |

REPOSITORIES: ENA

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Neuronal CD47 Induces Microglial Phagocytosis Defects and Autism-like Behaviors While Mitigating Aβ-Induced Synaptic Loss

Project description:Neuronal CD47 is a potent "do not eat me" signal that protects synapses from excessive pruning by microglia. We used an adeno-associated viruses gene expression system to induce neuron-specific CD47 overexpression in wild-type and 5xFAD mice,and we used single nucleus RNA sequencing (snRNA-seq) to analyze the diversity of neurons and microglia in the hippocampus.

2025-09-01 | GSE263398 | GEO

SELENOK-Dependent CD36 Palmitoylation Regulates Microglial Functions and Aβ Phagocytosis

Project description:Amyloid-beta (Aβ) is a key factor in the onset and progression of Alzheimer's disease (AD). Selenium (Se) compounds show promise in AD treatment. Here, we reveal that selenoprotein K (SELENOK), a selenoprotein involved in immune regulation and potentially related to AD pathology, plays a critical role in microglial immune response, migration, and phagocytosis. In vivo and in vitro studies corroborate that SELENOK deficiency inhibits microglial Aβ phagocytosis, exacerbating cognitive deficits in 5xFAD mice, which are reversed by SELENOK overexpression. Mechanistically, SELENOK is involved in CD36 palmitoylation through DHHC6, regulating CD36 localization to microglial plasma membranes and thus impacting Aβ phagocytosis. CD36 palmitoylation is reduced in the brains of AD patients and mice. Se supplementation promotes SELENOK expression and CD36 palmitoylation, enhancing microglial Aβ phagocytosis and mitigating AD progression. We have identified the regulatory mechanisms from Se-dependent selenoproteins to Aβ pathology, providing novel insights into potential therapeutic strategies involving Se and selenoproteins.

2024-02-29 | GSE255034 | GEO

IL4 promotes phagocytosis of murine leukemia cells counteracted by CD47 upregulation

Project description:Cytokines are key regulators of tumor immune surveillance by controlling immune cell activity. Here, we investigated whether interleukin 4 (IL4) has antileukemic activity via immune-mediated mechanisms in an in vivo murine model of acute myeloid leukemia driven by the MLL-AF9 fusion gene. Although IL4 strongly inhibited leukemia development in immunocompetent mice, the effect was diminished in immune-deficient recipient mice, demonstrating that the antileukemic effect of IL4 in vivo is dependent on the host immune system. Using flow cytometric analysis and immunohistochemistry, we revealed that the antileukemic effect of IL4 coincided with an expansion of F4/80+ macrophages in the bone marrow and spleen. To elucidate whether this macrophage expansion was responsible of the antileukemic effect, we depleted macrophages in vivo with clodronate liposomes. Macrophage depletion eliminated the antileukemic effect of IL4, showing that macrophages mediated the IL4-induced killing of leukemia cells. In addition, IL4 enhanced murine macrophage-mediated phagocytosis of leukemia cells in vitro. Global transcriptomic analysis of macrophages revealed an enrichment of signatures associated with alternatively activated macrophages and increased phagocytosis upon IL4 stimulation. Notably, IL4 concurrently induced Stat6-dependent upregulation of CD47 on leukemia cells, which suppressed macrophage activity. Consistent with this finding, combining CD47 blockade with IL4 stimulation enhanced macrophage-mediated phagocytosis of leukemia cells. Thus, IL4 has two counteracting roles in regulating phagocytosis in mice; enhancing macrophage-mediated killing of leukemia cells, but also inducing CD47 expression that protects target cells from excessive phagocytosis. Taken together, our data suggests that combined strategies that activate macrophages and block CD47 have therapeutic potential in AML.

2021-07-14 | GSE155048 | GEO

Transcriptional signature in microglia associated with Aβ plaque phagocytosis

Project description:Transcriptional signature in microglia associated with Aβ plaque phagocytosis

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SELENOK-Dependent CD36 Palmitoylation Regulates Microglial Functions and Aβ Phagocytosis

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HDX-MS Analysis of CD47 Conformational Dynamics

Project description:CD47 is the only 5-transmembrane (5-TM) spanning receptor of the immune system. Its extracellular domain (ECD) is a cell surface ‘marker of self’ that binds SIRPα and inhibits macrophage phagocytosis, and cancer immuno-therapy approaches in clinical trials are focused on blocking CD47/SIRPα interaction. Using hydrogen-deuterium exchange we show that CD47’s ECLR architecture, comprised of two extracellular loops and the SWF loop, creates a molecular environment stabilizing the ECD for presentation on the cell surface.

2021-07-15 | PXD026458 | Pride

CD47 blockade synergizes with doxorubicin in enhancing macrophage phagocytosis of Ewing sarcoma cells and deceasing xenograft tumor growth and metastasis in an orthotopic model of Ewing sarcoma

Project description:Macrophages are immune cells whose major functions include phagocytosing tumor cells. However, tumors escape macrophage phagocytosis through the expression of anti-phagocytic signals, most commonly CD47. Moreover, in Ewing sarcoma (ES), we found that tumor cells utilize dual mechanisms to evade macrophage clearance by simultaneously over-expressing CD47 and down-regulating cell surface calreticulin (csCRT), the pro-phagocytic signal. Here we utilize a CD47 blockade (magrolimab, MAG) to inhibit the anti-phagocytic signal and a chemotherapy regimen (doxorubicin, DOX) to enhance the pro-phagocytic signal and evaluated the effects of MAG or DOX alone and in combination on macrophage phagocytosis of ES cells in vitro and tumor formation and development in vivo. Furthermore, we performed RNA-Seq to identify potential mechanisms of resistance to the CD47 blockade combinatorial therapy.

2024-06-19 | GSE244548 | GEO

IL4 promotes phagocytosis of murine leukemia cells counteracted by CD47 upregulation

Project description:IL4 promotes phagocytosis of murine leukemia cells counteracted by CD47 upregulation

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Human single nuclear RNA sequencing identifies CD47 as a therapeutic target for doxorubicin-induced cardiomyopathy

Project description:Doxorubicin cardiomyopathy (DoxCM) remains a significant clinical problem, yet its underlying mechanisms remain incompletely understood. Identifying DoxCM mechanisms that can be translated into therapeutic interventions may improve patient outcomes. We performed single nuclear RNA-sequencing on left ventricular (LV) myocardial tissue from patients with DoxCM versus non-ischemic cardiomyopathy and non-failing donors. This approach aimed to elucidate the transcriptional changes associated with DoxCM. Additionally, we conducted immunostaining, flow cytometry, antibody neutralization, and cell depletion studies to validate our findings and define in vivo mechanisms.Compared to both donors and non-ischemic cardiomyopathy, LV myocardium from DoxCM patients exhibited increased periostin-positive (POSTN+) activated fibroblasts, down-regulation of genes involved in phagocytosis, and increased expression of the anti-phagocytic molecule CD47. Immunostaining of human cardiac sections and murine studies demonstrated increased POSTN+ cells and CD47 in DoxCM and in a murine breast cancer model. CD47 antibody neutralization both prevented and treated Dox-induced reduction in LV ejection fraction and fibrosis. Mechanistically, depletion of resident cardiac macrophages blocked the cardioprotective effects of CD47 neutralization and clearance of cardiac fibroblasts. Our data support CD47 as a disease-specific target and promising therapeutic approach for mitigating cardiac dysfunction in DoxCM

2025-08-18 | GSE292067 | GEO

CD47 Expression in Solid Tumors Correlates with Phagocytic Tumor-Associated Macrophage Gene Signature

Project description:CD47 is a “don’t eat me” signal that is frequently overexpressed in tumors to evade phagocytosis by tumor associated macrophages (TAM). Investigational agents targeting CD47, such as magrolimab, aim to induce phagocytosis of tumor cells by TAMs. Previously, two functionally defined key TAM subsets have been identified: complement C1q C chain positive (C1QC) TAMs, which display pro-phagocytic activity, and secreted phosphoprotein 1 positive (SPP1) TAMs that express pro-angiogenic markers. Here we characterize CD47 expression and its relationship with tumor macrophages in solid tumor samples.

2025-09-04 | GSE296861 | GEO

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