Integrative Proteome, Transcriptome and DNA Methylome Analysis of Regulatory Networks During U937-derived Macrophage Polarization from an M2 to M1 Phenotype
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE128007 | GEO | 2021/08/19
REPOSITORIES: GEO
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Project description:Tumor associate macrophages (TAMs) depletion or re-education towards an antitumor effector phenotype are considered a promising cancer therapeutic approach. However, the underlying molecular mechanisms remain unclear. Here, we apply proteome, transcriptome and DNA methylome to assay the regulatory networks during polarization of U937-derived macrophages transitioning from an M2 to M1 phenotype.
2021-08-18 | GSE127981 | GEO
Project description:We report the application of MeDIP sequencing technology for high-throughput profiling of M2 and M1 phenotype U937 cells. A total of 260 differentially methylated regions (DMRs) within promotor regions were identified, with 191 hyper-methylated and 69 hypo-methylated every chromosome. These DMRs were then further examined using GO analysis, with the top10 most enriched GO terms for both the hyper- and hypo-methylation groups isolated. The processes associated with hyper-methylation included the regulation of protein processes (targeting, processing, maturation and localization) and tyrosine phosphorylation of STAT5 protein, while the hypo-methylated processes included the regulation of epithelial to mesenchymal transition, mesenchymal cell differentiation and epithelial to mesenchymal transition. When further analyzing the regulation of tyrosine STAT5 phosphorylation, three associated genes (IL-31RA, IL-3, and NF2) previous shown to be associated with tumor or cancer development were also identified, thus suggesting that hyper-methylation may be important during M2 polarization into M1 cells. The epithelial to mesenchymal transition (EMT) process has been long accepted to be associated with cancer metastasis and malignance. Herein, four genes (TGFB1I1, TWIST1, HPN, and PHLDB2) that have been previously reported to participate in cancer invasion and metastasis were hypo-methylated during the EMT process, thus suggesting that these hypo-methylation sites might be a potential therapeutic target to control cancer metastasis. Moreover, the hyper-methylation was found to be predominantly localized to membranes, including the leading edge membrane, whole membrane, endoplasmic reticulum-Golgi intermediate compartment membrane, recycling endosome membrane and ruffle membrane, whereas the hypo-methylation was predominantly localized to the cytoskeleton, cell junction and cell cortex. These findings also suggest a potential ability for epigenetic therapy due to both the membrane and cytoskeleton being feasible targets for therapeutic chemical or antibody targeting. When performing pathway enrichment analysis for the hyper-methylated genes, fatty acid biosynthesis, ubiquitin mediated proteolysis, mRNA surveillance and AMPK signaling pathways were enriched; while for the hypo-methylated genes, pathways associated with cancers, such as tight junction, VEGF signaling, cAMP signaling, proteoglycans and Ras signaling pathways were enriched during polarization from M2 to M1 cells
2022-03-01 | GSE128006 | GEO
Project description:Integrative Proteome, Transcriptome and DNA Methylome Analysis of Regulatory Networks During U937-derived Macrophage Polarization from an M2 to M1 Phenotype
| PRJNA526041 | ENA
Project description:Integrative Proteome, Transcriptome and DNA Methylome Analysis of Regulatory Networks During U937-derived Macrophage Polarization from an M2 to M1 Phenotype [array]
| PRJNA525980 | ENA
Project description:Integrative Proteome, Transcriptome and DNA Methylome Analysis of Regulatory Networks During U937-derived Macrophage Polarization from an M2 to M1 Phenotype [MeDIP-Seq]
| PRJNA526045 | ENA
Project description:Macrophages are key participants in melanoma growth and survival. In general, macrophages can be classified as M1 or M2 activation phenotypes. Increasing evidence demonstrates that melanoma exosomes also facilitate tumor survival and metastasis. However, the role of melanoma exosomes in directly influencing macrophage function is poorly understood. Herein, we investigated the hypothesis that natural melanoma exosomes might directly influence macrophage polarization. To explore this hypothesis, ELISA, RT-qPCR, and macrophage functional studies were performed in vitro using an established source of melanoma exosomes (B16-F10). ELISA results for melanoma exosome induction of common M1 and M2 cytokines in RAW 264.7 macrophages, revealed that melanoma exosomes do not polarize macrophages exclusively in the M1 or M2 direction. Melanoma exosomes induced the M1 and M2 representative cytokines TNF-? and IL-10 respectively. Further assessment, using an RT-qPCR array with RAW 264.7 and primary macrophages, confirmed and extended the ELISA findings. Upregulation of markers common to both M1 and M2 polarization phenotypes included CCL22, IL-12B, IL-1?, IL-6, i-NOS, and TNF-?. The M2 cytokine TGF-? was upregulated in primary but not RAW 264.7 macrophages. Pro-tumor functions have been attributed to each of these markers. Macrophage functional assays demonstrated a trend toward increased i-NOS (M1) to arginase (M2) activity. Collectively, the results provide the first evidence that melanoma exosomes can induce a mixed M1 and M2 pro-tumor macrophage activation phenotype.
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Project description:Calcium oxalate (CaOx) crystal can trigger kidney injury, which contributes to the pathogenesis of nephrocalcinosis. The phenotypes of infiltrating macrophage may impact CaOx-mediated kidney inflammatory injury as well as crystal deposition. How aryl hydrocarbon receptor (AhR) regulates inflammation and macrophage polarization is well understood; however, how it modulates CaOx nephrocalcinosis remains unclear. Methods: Mice were intraperitoneally injected with glyoxylate to establish CaOx nephrocalcinosis model with or without the treatment of AhR activator 6-formylindolo(3,2-b)carbazole (FICZ). Positron emission tomography computed tomography (PET-CT) imaging, Periodic acid-Schiff (PAS) staining, and polarized light optical microscopy were used to evaluate kidney injury and crystal deposition in mice kidney. Western blotting, immunofluorescence, chromatin immunoprecipitation, microRNA-fluorescence in situ hybridization, and luciferase reporter assays were applied to analyze polarization state and regulation mechanism of macrophage. Results: AhR expression was significantly upregulated and negatively correlated with interferon-regulatory factor 1 (IRF1) and hypoxia inducible factor 1-alpha (HIF-1α) levels in a murine CaOx nephrocalcinosis model following administration of FICZ. Moreover, AhR activation suppressed IRF1 and HIF-1α levels and decreased M1 macrophage polarization in vitro. In terms of the mechanism, bioinformatics analysis and chromatin immunoprecipitation assay confirmed that AhR could bind to miR-142a promoter to transcriptionally activate miR-142a. In addition, luciferase reporter assays validated that miR-142a inhibited IRF1 and HIF-1α expression by directly targeting their 3'-untranslated regions. Conclusions: Our results indicated that AhR activation could diminish M1 macrophage polarization and promote M2 macrophage polarization to suppress CaOx nephrocalcinosis via the AhR-miR-142a-IRF1/HIF-1α pathway.
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Project description:The majority of the immune cell population in the tumor microenvironment (TME) consists of tumor-associated macrophages (TAM), which are the main players in coordinating tumor-associated inflammation. TAM has a high plasticity and is divided into two main phenotypes, pro-inflammatory M1 type and anti-inflammatory M2 type, with tumor-suppressive and tumor-promoting functions, respectively. Considering the beneficial effects of M1 macrophages for anti-tumor and the high plasticity of macrophages, the conversion of M2 TAM to M1 TAM is feasible and positive for tumor treatment. This study sought to evaluate whether the glycopeptide derived from simulated digested Codonopsis pilosula extracts could regulate the polarization of M2-like TAM toward the M1 phenotype and the potential regulatory mechanisms. The results showed that after glycopeptide dCP1 treatment, the mRNA relative expression levels of some M2 phenotype marker genes in M2-like TAM in simulated TME were reduced, and the relative expression levels of M1 phenotype marker genes and inflammatory factor genes were increased. Analysis of RNA-Seq of M2-like TAM after glycopeptide dCP1 intervention showed that the gene sets such as glycolysis, which is associated with macrophage polarization in the M1 phenotype, were significantly up-regulated, whereas those of gene sets such as IL-6-JAK-STAT3 pathway, which is associated with polarization in the M2 phenotype, were significantly down-regulated. Moreover, PCA analysis and Pearson's correlation also indicated that M2-like TAM polarized toward the M1 phenotype at the transcriptional level after treatment with the glycopeptide dCP1. Lipid metabolomics was used to further explore the efficacy of the glycopeptide dCP1 in regulating the polarization of M2-like TAM to the M1 phenotype. It was found that the lipid metabolite profiles in dCP1-treated M2-like TAM showed M1 phenotype macrophage lipid metabolism profiles compared with blank M2-like TAM. Analysis of the key differential lipid metabolites revealed that the interconversion between phosphatidylcholine (PC) and diacylglycerol (DG) metabolites may be the central reaction of the glycopeptide dCP1 in regulating the conversion of M2-like TAM to the M1 phenotype. The above results suggest that the glycopeptide dCP1 has the efficacy to regulate the polarization of M2-like TAM to M1 phenotype in simulated TME.
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Project description:Tumor tissues are characterized by an elevated interstitial fluid flow from the tumor to the surrounding stroma. Macrophages in the tumor microenvironment are key contributors to tumor progression. While it is well established that chemical stimuli within the tumor tissues can alter macrophage behaviors, the effects of mechanical stimuli, especially the flow of interstitial fluid in the tumor microenvironment, on macrophage phenotypes have not been explored. Here, we used three-dimensional biomimetic models to reveal that macrophages can sense and respond to pathophysiological levels of interstitial fluid flow reported in tumors (∼3 µm/s). Specifically, interstitial flow (IF) polarizes macrophages toward an M2-like phenotype via integrin/Src-mediated mechanotransduction pathways involving STAT3/6. Consistent with this flow-induced M2 polarization, macrophages treated with IF migrate faster and have an enhanced ability to promote cancer cell migration. Moreover, IF directs macrophages to migrate against the flow. Since IF emanates from the tumor to the surrounding stromal tissues, our results suggest that IF could not only induce M2 polarization of macrophages but also recruit these M2 macrophages toward the tumor masses, contributing to cancer cell invasion and tumor progression. Collectively, our study reveals that IF could be a critical regulator of tumor immune environment.
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