Unknown,Transcriptomics,Genomics,Proteomics

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Transcriptional study of the response of murine bone marrow-derived macrophages to TLR4 stimulation with LPS

ABSTRACT: Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipid-loaded macrophages in the arterial wall. Intimal macrophages internalize modified lipoproteins such as oxidized LDL (oxLDL) through scavenger receptors, leading to storage of excess cholesteryl esters in lipid bodies and a "foam cell" phenotype. In addition, stimulation of macrophage Toll-like receptors (TLRs) has been shown to promote lipid body proliferation. We investigated the possibility that there are transcriptional regulators that are common to both pathways for stimulating foam cell formation (modified lipoproteins and TLR stimulation), and identified the transcription factor ATF3 as a candidate regulator. In this specific microarray experiment, we studied the transcriptional response of murine macrophages to stimulation with the TLR4 agonist, LPS. Bone marrow-derived macrophages from C57BL/6J mice were incubated in the presence or absence of LPS for 4 h, and then transcriptionally profiled using the Affymetrix Mouse Exon Array 1.0 ST. The goal was to study the pattern of transcript-level differential expression between the unstimulated and LPS-stimulated cells. Three female mice (strain C57BL/6J) were sacrificed at 8-12 weeks of age, and macrophages were derived from the femoral bone marrow using rhM-CSF. On day six, macrophages were divided into two treatment groups per animal, for a total of six samples. LPS was introduced into the medium for three samples (one from each animal) at 10 ng/mL on day seven, and after 4 h of incubation, RNA was isolated using Trizol. Labeled cRNA derived from the RNA samples was hybridized to Affymetrix Mouse Exon Array 1.0 ST GeneChips. Microarray data were processed using transcript-level probesets, and are in log2 scale.

ORGANISM(S): Mus musculus

SUBMITTER: Alan Aderem

PROVIDER: E-GEOD-32359 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipid-loaded macrophages in the arterial wall. Intimal macrophages internalize modified lipoproteins such as oxidized LDL (oxLDL) through scavenger receptors, leading to storage of excess cholesteryl esters in lipid bodies and a "foam cell" phenotype. In addition, stimulation of macrophage Toll-like receptors (TLRs) has been shown to promote lipid body proliferation. We investigated the possibility that there are transcriptional regulators that are common to both pathways for stimulating foam cell formation (modified lipoproteins and TLR stimulation), and identified the transcription factor ATF3 as a candidate regulator. In this specific microarray study, we re-analyzed a subset of the data from a 2006 microarray experiment (Gilchrist et al., Nature, 441:173-178, 2006) in which wild-type and Atf3-/- murine macrophages were stimulated with LPS. The goal of this analysis was to identify genes whose LPS responses are significantly affected by loss of ATF3 in macrophages, using up-to-date genome annotations. The raw microarray data files included in this submission were originally released to the public as a part of a larger microarray dataset that accompanied the Gilchrist et al. study (ArrayExpress accession # E-TABM-102). These data were re-analyzed using the CustomCDF v13 ENSG probesets as a part of a transcriptomic study of the response of macrophages to stimuli, including LPS, that induce foam cell formation (see GSE32358 and GSE32359). In the Gilchrist study, the experiment design was as follows: Female mice of the indicated strains were sacrificed at 8-12 weeks of age, and macrophages were derived from the femoral bone marrow using rhM-CSF. On day six, macrophages were plated and LPS introduced into the medium as indicated. After four hours, RNA was isolated using Trizol. Labeled cRNA derived from the RNA samples was hybridized to Affymetrix Mouse Genome 430 2.0 GeneChips. For the current study, probe-level instensity data were re-processed using gene-level probesets from the CustomCDF project (ENSG, v13), and are in log2 scale.

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Transcriptional study of the response of murine bone marrow-derived macrophages to TLR4 stimulation with LPS

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