Unknown,Transcriptomics,Genomics,Proteomics

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Transcriptome-based network analysis reveals a spectrum model of human macrophage activation [ChIP-Seq]

ABSTRACT: Macrophage activation is associated with profound transcriptional reprogramming. Although much progress has been made in the understanding of macrophage activation, polarization and function, the transcriptional programs regulating these processes remain poorly characterized. We stimulated human macrophages with diverse activation signals, acquiring a dataset of 299 macrophage transcriptomes. Analysis of this dataset revealed a spectrum of macrophage activation states extending the current M1 versus M2-polarization model. Network analyses identified central transcriptional regulators associated with all macrophage activation complemented by regulators related to stimulus-specific programs. Applying these transcriptional programs to human alveolar macrophages from smokers and patients with chronic obstructive pulmonary disease (COPD) revealed an unexpected loss of inflammatory signatures in COPD patients. Finally, by integrating murine data from the ImmGen project we propose a refined, activation-independent core signature for human and murine macrophages. This resource serves as a framework for future research into regulation of macrophage activation in health and disease. To better understand active gene regulation in human macrophages during activation and differentiation in vitro with different stimuli ChIP-sequencing experiments were performed. Enrichment patterns of the permissive histone modification mark trimetylation of histone protein 3 (H3K4me3) and macrophage lineage-specific transcription factor PU.1 were analyzed.

ORGANISM(S): Homo sapiens

SUBMITTER: Joachim Schultze

PROVIDER: E-GEOD-47188 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Transcriptome-based network analysis reveals a spectrum model of human macrophage activation.

Xue Jia J Schmidt Susanne V SV Sander Jil J Draffehn Astrid A Krebs Wolfgang W Quester Inga I De Nardo Dominic D Gohel Trupti D TD Emde Martina M Schmidleithner Lisa L Ganesan Hariharasudan H Nino-Castro Andrea A Mallmann Michael R MR Labzin Larisa L Theis Heidi H Kraut Michael M Beyer Marc M Latz Eicke E Freeman Tom C TC Ulas Thomas T Schultze Joachim L JL

Immunity 20140213 2

Macrophage activation is associated with profound transcriptional reprogramming. Although much progress has been made in the understanding of macrophage activation, polarization, and function, the transcriptional programs regulating these processes remain poorly characterized. We stimulated human macrophages with diverse activation signals, acquiring a data set of 299 macrophage transcriptomes. Analysis of this data set revealed a spectrum of macrophage activation states extending the current M1 ...[more]

PMID: 24530056

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Project description:Microvesicles (MV) are small membrane-bound particles comprised of exosomes and various sized extracellular vesicles. These are released by a number of cell types. Microvesicles have a variety of cellular functions from communication to mediating growth and differentiation. Microvesicles contain proteins and nucleic acids. Previously, we showed that plasma microvesicles contain microRNAs (miRNAs). Based on our previous report, the majority of peripheral blood microvesicles are derived from platelets while mononuclear phagocytes, including macrophages, are the second most abundant population. Here, we characterized macrophage-derived microvesicles and whether they influenced the differentiation of naM-CM-/ve monocytes. We also identified the miRNA content of the macrophage-derived microvesicles. We found that RNA molecules contained in the macrophage-derived microvesicles were transported to target cells, including monocytes, endothelial cells, epithelial cells and fibroblasts. Furthermore, we found that miR-223 was transported to target cells and was functionally active. Based on our observations, we hypothesize that microvesicles bind to and activate target cells. Furthermore, we find that microvesicles induce the differentiation of macrophages. Thus, defining key components of this response may identify novel targets to regulate host defense and inflammation. We used GeneChip microarrays to examine changes in gene expression induced by MV in primary monocyte-derived macrophages (MDM) and in THP1 cells, and compare this to cells treated with GM-CSF and PMA, respectively. All experiments were done in triplicates. Primary monocytes were collected from buffy coats (BC). The freshly isolated monocytes from three donors (Mono1-3) were either treated with GM-CSF or subjected to RNA isolation. Following treatment, MVs were isolated from the GM-CSF-treated macrophage cultures. RNA was isolated from the remaining cells for profiling (GM1-3). The isolated MVs were then used to treat new BC monocytes for 24 h (BC-GMCSF-MV24). A fraction of the new BC monocytes was subjected to RNA extraction for profiling (BC1-3). For THP1 cells, they were treated with either DMSO or PMA to produce MVs. The MVs were collected and the remaining cells lyzed for RNA extraction and profiling (DMSO1-3 and PMA1-3). The collected MVs from the DMSO or PMA-treated THP1 cells were incubated with new THP1 for 24 h and designated DMSO-MV24 or PMA-MV24. We had a total of 24 samples.

Dataset Information

Transcriptome-based network analysis reveals a spectrum model of human macrophage activation [ChIP-Seq]

Publications

Transcriptome-based network analysis reveals a spectrum model of human macrophage activation.

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