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Effect of ApoE in communicating CD4+ T cell activation and proliferation

ABSTRACT: While ApoE expression by myeloid cells is recognized to control inflammation, whether such benefits can be communicated via extracellular vesicles including exosomes is not known. Through the study of exosomes produced by macrophages derived from the bone marrow of Wildtype (WT-BMDM-exo) and ApoE deficient (EKO-BMDM-exo) mice, we uncover a critical role of ApoE in regulating cell signaling properties. We treated splenic CD4+ T cells with EKO-BMDM-exo, WT-BMDM-exo, or PBS and performed gene expression profiling analysis. We found that CD4+ T cells treated with EKO-BMDM-exo show elevations in genes involved in the T-cell receptor complex (Cd3e, Cd247, & Cd4) and Il2rg, a key component of cytokine receptors on CD4+ T cells. Taken together, our data unveil a novel property of macrophage ApoE in controlling adaptive immunity by their secreted exosomes.

ORGANISM(S): Mus musculus

PROVIDER: GSE237731 | GEO | 2023/08/23

REPOSITORIES: GEO

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Effect of ApoE deficiency on microRNA expression in bone marrow derived macrophages (BMDM)

Project description:ApoE exerts pleiotropic properties in controlling inflammation and myeloid cell activation. We here uncover microRNA regulation as yet another mechanism that ApoE acts upon to control immune cell activity and inflammatory response. We compared the expression of microRNAs in BMDM derived from ApoE-KO (EKO) or WIldtype (WT) mice and identified 78 microRNAs to be differentially expressed between these two groups. Among these microRNAs, we identified miR-146a-5p to be highly upregulated in WT BMDM as compared to EKO BMDM. This is consistent with our prior study that reports a role of ApoE in promoting the biogenesis of this microRNA via the transcription of its host gene PU.1 (Spi1) in monocytes/macrophages. Of note, miR-146a-5p is recognized as a potent inhibitor of the NF-κB signaling pathway via the inactivation of IRAK1 and TRAF6. Furthermore, we identified mIR-142a-3p as downregulated in WT BMDM as compared to EKO BMDM. This microRNA has been reported to control important metabolic functions in myeloid cells by targeting the long chain fatty acid transporter CPT1A, thereby inhibiting fatty acid oxidation. Our data thus uncovers another novel of ApoE in controlling lipid metabolism in myeloid cells by suppressing the expression of miR-142a-3p. Taken together, our data provide a novel framework for the microRNA signatures regulated by ApoE in myeloid cells. Moreover, we uncovered an important mechanism of which ApoE can regulate myeloid cell immunometabolism via the regulation of miR-146a-5p and miR-142a-3p.

2023-08-23 | GSE237727 | GEO

High Glucose Macrophage Exosomes Enhance Atherosclerosis by Driving Cellular Proliferation & Hematopoiesis [RNA-Seq]

Project description:Hyperglycemia is a recognized risk factor for cardiovascular complications in diabetes. While hyperglycemia is known to cause microRNA dysregulation that contributes to cellular activation, whether it can do so through intercellular communication via extracellular vesicles (EVs) is not known. We investigated whether EVs produced under hyperglycemic conditions could communicate signaling to drive atherosclerosis. We did so by treating Apoe−/−mice with exosomes produced by bone marrow‐derived macrophages (BMDM) exposed to high glucose (BMDM–HG-exo) or control. Repeated infusion of BMDM–HG-exo led to a robust increase in hematopoiesis leading to augmented circulating myeloid cell numbers. Four weeks of BMDM–HG-exo infusions increased atherosclerotic lesion sizes with an accumulation of macrophage and apoptotic cells in the aortic root. Transcriptome-wide analysis of naïve cultured macrophages treated with BMDM–HG-exo showed an upregulation of genes associated with cell proliferation. Furthermore, BMDM–HG-exo reprogramed energy metabolism in recipient macrophages with an upregulation of glycolytic activity. Plasma EVs isolated from human subjects with type II diabetes exerted similar cell signaling when incubated with cultured human macrophages. Lastly, profiling microRNA in BMDM–HG-exo and human diabetic plasma EVs converged on miR-486 as commonly enriched. In conclusion, our findings show that EVs serve to communicate detrimental

2021-08-18 | GSE162961 | GEO

High Glucose Macrophage Exosomes Enhance Atherosclerosis by Driving Cellular Proliferation & Hematopoiesis [miRNA-Seq]

2021-08-18 | GSE162958 | GEO

Macrophage Exosomes Resolve Atherosclerosis by Regulating Hematopoiesis and Inflammation via MicroRNA Cargo

Project description:Developing strategies that promote the resolution of vascular inflammation and atherosclerosis remains a major therapeutic challenge. Here, we show that exosomes produced by naive bone marrow-derived macrophages (BMDM-exo) contain anti-inflammatory microRNA-99a/146b/378a that are further increased in exosomes produced by BMDM polarized with IL-4 (BMDM-IL-4-exo). These exosomal microRNAs suppress inflammation by targeting NF-kB and TNF-a signaling and foster M2 polarization in recipient macrophages. Repeated infusions of BMDM-IL-4-exo into Apoe_x0001_/_x0001_ mice fed a Western diet reduce excessive hematopoiesis in the bone marrow and thereby the number of myeloid cells in the circulation and macrophages in aortic root lesions. This also leads to a reduction in necrotic lesion areas that collectively stabilize atheroma. Thus, BMDM-IL-4-exo may represent a useful therapeutic approach for atherosclerosis and other inflammatory disorders by targeting NF-kB and TNF-a via microRNA cargo delivery.

2020-08-06 | GSE155745 | GEO

Exosomal microRNA sequencing in Tongxinluo pretreated and non-treated MSC-derived exosomes

Project description:In order to investigate the specific mechanisms underlying the cardioprotective effects of Tongxinluo pretreated MSC-derived exosomes (MSCTXL-Exo) in cardiac repair, we performed microRNA sequencing on exosomes secreted from Tongxinluo pretreated MSCs and non-treated MSCs to identify differentially expressed miRNA. We found that 18 miRNAs were identified to be upregulated and 25 miRNAs downregulated (over 2-fold change) in MSCTXL-Exo compared to MSC-Exo.

2022-06-01 | GSE184067 | GEO

Exosomal lncRNA sequencing in Atorvastatin treated and non-treated MSC-derived exosomes

Project description:In order to investigate the molecular mechanisms underlying the further enhancement of Atorvastatin pretreated MSC-derived exosomes (MSCATV-Exo) in cardiac protection, we performed lncRNA sequencing on exosomes secreted from ATV pretreated MSCs and non treated MSCs to identify differentially expressed lncRNA. We found that 450 lncRNAs were identified to be upregulated and 1332 lncRNAs downregulated (over 1.5 fold change) in MSCATV-Exo compared to MSC-Exo.

2019-02-28 | GSE113570 | GEO

A customizable purification assay designed for small-RNA biomarker identification and functional evaluation of circulating exosomes: Exosome Capture by AnTibody of CHoice and Enzymatic Release (exo-CATCHER)

Project description:Circulating nucleic acids, encapsulated within exosomes, can provide a remote cellular snapshot of biomarkers associated with disease, however selective exosome isolation is critical. Current laboratory-based purification techniques rely on the physical properties of exosomes for selection, rather than their inherited cellular characteristics. Therefore, we established a highly selective purification assay, termed exosome Capture by AnTibody of CHoice and Enzymatic Release (exo-CATCHER), designed for high-throughput analysis of low-abundance small-RNA cargos by next-generation sequencing. We demonstrated its sensitivity by specifically isolating and sequencing small-RNA from mouse exosomes spiked into human plasma. Furthermore, we used Western blotting, nanoparticle tracking, and transmission electron microscopy to validate, quantify, and demonstrate capture and release of intact exosomes. As proof of principle, we utilized exo-CATCHER to purify serum exosomes from mildly and severely ill Covid-19 patients, identified, and validated hsa-miR-146a and hsa-miR-126-3p to be significantly downregulated in a small sample set of severely ill patients. We used exo-CATCHER to purify intact exosomes from high IgG titer convalescent sera and confirmed unexpected neutralizing properties, against SARS-CoV-2 in vitro, identified using ultracentrifuged exosomes, not observable with exosomes from sera with IgG titers below quantification level. Exo-CATCHER represents a versatile molecular assay for highly specific purification of circulating exosomes.

2021-05-13 | GSE158948 | GEO

HO-1/BMMSCs exosomes treating inflammatory injured IEC-6 cells LC-MSMS

Project description:In this study, we established a rat small intestinal cell (IEC-6) injury model with tumor necrosis factor-α (TNF-α). Then, we added the exosomes from TNF- α damaged IEC-6 (TNF-α-exo), co-cultured with BMMSCs exosomes (BM-exo) and heme oxygenase-1 modified BMMSCs (HBM-exo) system exosomes into IEC-6 cells injured by TNF- α inflammation. After 48 hours, IEC-6 cells were collected for proteomic detection.

2020-06-29 | PXD017002 | Pride

Aortic gene expression profiles show how APOA-I levels modulate infammation, lysosomal activity and sphingolipid metabolism in murine atherosclerosis

Project description:HDL particles are known to possess several anti-atherogenic properties that include the removal of excess cholesterol from peripheral tissues, the maintenance of endothelial integrity, antioxidant and antiinflammatory activities. ApoA-I overexpression in apoE-deficient (EKO) mice has been shown to increase HDL levels and to strongly reduce atherosclerosis development. The aim of the study was to investigate gene expression patterns associated with atherosclerosis development in the aorta of EKO mice and how HDL plasma levels relate to gene expression patterns at different stages of atherosclerosis development and with different dietary treatments. Methods Eight weeks old EKO mice, EKO mice overexpressing human apoA-I (EKO/hA-I) and wild-type mice as controls were fed either Chow or Western diet for 6 or 22 weeks. Cholesterol distribution among lipoproteins was evaluated and atherosclerosis of the aorta was quantified. High-throughput sequencing technologies were used to analyse the transcriptome of the aorta of the three genotypes in each experimental condition. Results: In addition to the well-known activation of inflammation and immune response, the impairment of sphingolipid metabolism, phagosome-lysosome system and osteoclast differentiation emerged as relevant players in atherosclerosis development. The reduced atherosclerotic burden in the aorta of EKO mice expressing high levels of apoA-I was accompanied by a reduced activation of the immune system markers, as well as reduced perturbation of lysosomal activity and a better regulation of the sphingolipid synthesis pathway Conclusions. ApoA-I modulates atherosclerosis development in the aorta of EKO mice affecting the expression of pathways additional to those associated with inflammation and immune response

2020-12-22 | GSE163657 | GEO

microRNA profiles of nasopharyngeal carcinoma cell line and nasopharyngeal epithelial cell line

Project description:Exosomal and cellular miRNA expression levels were measured using a microRNA chip array or quantitative reverse transcription PCR (qRT-PCR). miR-24-3p was enriched in T-EXOs from the sera of NPC patients and NPC cells, which was correlated with worse disease-free survival (DFS). Exosomes (miR-24-3p-sponge-EXO) released from miR-24-3p-sponge-TW03 cells failed to inhibit T-cell proliferation and Th1 and Th17 differentiation or to induce Treg differentiation in vitro, compared with controlNC -sponge-EXO. Mechanistic analyses revealed that in miR-24-3p-sponge-EXO-treated T-cells, P-ERK, P-STAT1 and P-STAT3 were up-regulated, whereas P-STAT5 was down-regulated compared with controlNC-sponge-EXO-treated T-cells. FGF11 was identified as a direct target gene of miR-24-3p through in vivo and in vitro assessments. More importantly, the T-EXOs repressed FGF11 expression in T-cells during proliferation and differentiation. Interestingly, when FGF11 expression in T-cells was blocked, miR-24-3p-sponge-EXOs impeded shFGF11-T-cell proliferation and Th1 and Th17 differentiation but induced Treg differentiation, like controlNC-sponge-EXO. When FGF11 was knocked down in miR-24-3p-sponge-EXO-treated T-cells, neither P-ERK, P-STAT1 and P-STAT3 up-regulation or P-STAT5 down-regulation occurred. Interestingly, FGF11 expression in tumor-infiltrating lymphocytes (TILs) was significantly and positively correlated with the number of CD4+ and CD8+ TILs and predicted favorable DFS of the patients (p < 0.05). Two-condition experiment, one nasopharyngeal carcinoma cell line TW03 vs. one normal epithelium cell line NP69. Biological replicates: 1 nasopharyngeal carcinoma cell line TW03; 1 nasopharyngeal epithelial cell line NP69.

2016-08-01 | E-GEOD-76527 | biostudies-arrayexpress

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