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A novel model of common Toll-like receptor 4- and injury-induced transcriptional themes in human leukocytes.

ABSTRACT: An endotoxin challenge, sepsis, and injury/trauma, trigger significant changes in human peripheral blood leukocytes (PBL) gene expression. In this study, we have sought to test the hypothesis that the Toll-like receptor 4 (TLR4) induced transcription patterns elicited in humans exposed to in vivo endotoxin would parallel gene expression patterns observed in trauma patients with initial non-infectious injury. In addition, we sought to identify functional modules that are commonly affected by these two insults of differing magnitude and duration.PBL were obtained from seven adult human subject experimental groups. The groups included a group of healthy, hospitalized volunteers (n = 15), that comprised four study groups of subjects challenged with intravenous endotoxin, without or with cortisol, and two serial samplings of trauma patients (n = 5). The PBL were analyzed for gene expression using a 8,793 probe microarray platform (Gene Chip® Focus, Affymetrix). The expression of a subset of genes was determined using qPCR.We describe sequential selection criteria of gene expression data that identifies 445 genes that are significantly differentially expressed (both P ? 0.05 and > 1.2 fold-change) in PBL derived from human subjects during the peak of systemic inflammatory responses induced by in vivo endotoxin, as well as in PBL obtained from trauma patients at 1 to 12 days after admission. We identified two functional modules that are commonly represented by this analysis. The first module includes more than 50 suppressed genes that encode ribosomal proteins or translation regulators. The second module includes up-regulated genes encoding key enzymes associated with glycolysis. Finally, we show that several circadian clock genes are also suppressed in PBL of surgical ICU patients.We identified a group of > 400 genes that exhibit similar expression trends in PBL derived from either endotoxin-challenged subjects or trauma patients. The suppressed translational and circadian clock modules, and the upregulated glycolytic module, constitute a robust and long lasting PBL gene expression signature that may provide a tool for monitoring systemic inflammation and injury.

SUBMITTER: Haimovich B

PROVIDER: S-EPMC3219281 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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A novel model of common Toll-like receptor 4- and injury-induced transcriptional themes in human leukocytes.

Haimovich Beatrice B Reddell Michael T MT Calvano Jacqueline E JE Calvano Steve E SE Macor Marie A MA Coyle Susette M SM Lowry Stephen F SF

Critical care (London, England) 20101007 5

<h4>Introduction</h4>An endotoxin challenge, sepsis, and injury/trauma, trigger significant changes in human peripheral blood leukocytes (PBL) gene expression. In this study, we have sought to test the hypothesis that the Toll-like receptor 4 (TLR4) induced transcription patterns elicited in humans exposed to in vivo endotoxin would parallel gene expression patterns observed in trauma patients with initial non-infectious injury. In addition, we sought to identify functional modules that are comm ...[more]

PMID: 20929567

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Project description:Mohan A, Malur A, McPeek M, Barna BP, Schnapp LM, Thomassen MJ, Gharib SA. Transcriptional survey of alveolar macrophages in a murine model of chronic granulomatous inflammation reveals common themes with human sarcoidosis. Am J Physiol Lung Cell Mol Physiol 314: L617-L625, 2018. First published December 6, 2017; doi: 10.1152/ajplung.00289.2017 . To advance our understanding of the pathobiology of sarcoidosis, we developed a multiwall carbon nanotube (MWCNT)-based murine model that shows marked histological and inflammatory signal similarities to this disease. In this study, we compared the alveolar macrophage transcriptional signatures of our animal model with human sarcoidosis to identify overlapping molecular programs. Whole genome microarrays were used to assess gene expression of alveolar macrophages in six MWCNT-exposed and six control animals. The results were compared with the transcriptional profiles of alveolar immune cells in 15 sarcoidosis patients and 12 healthy humans. Rigorous statistical methods were used to identify differentially expressed genes. To better elucidate activated pathways, integrated network and gene set enrichment analysis (GSEA) was performed. We identified over 1,000 differentially expressed between control and MWCNT mice. Gene ontology functional analysis showed overrepresentation of processes primarily involved in immunity and inflammation in MCWNT mice. Applying GSEA to both mouse and human samples revealed upregulation of 92 gene sets in MWCNT mice and 142 gene sets in sarcoidosis patients. Commonly activated pathways in both MWCNT mice and sarcoidosis included adaptive immunity, T-cell signaling, IL-12/IL-17 signaling, and oxidative phosphorylation. Differences in gene set enrichment between MWCNT mice and sarcoidosis patients were also observed. We applied network analysis to differentially expressed genes common between the MWCNT model and sarcoidosis to identify key drivers of disease. In conclusion, an integrated network and transcriptomics approach revealed substantial functional similarities between a murine model and human sarcoidosis particularly with respect to activation of immune-specific pathways.

Project description:Rationale: A well-validated animal model of sarcoidosis can help advance our understanding of the pathobiology of this complex disease. We have developed a multiwall carbon nanotube (MWCNT) based murine model that shows marked histological and inflammatory signal similarities to human sarcoidosis. In this study, we compared the alveolar immune cell transcriptional signatures of our murine model with human sarcoidosis to comprehensively assess overlapping molecular programs. Methods: Total RNA was extracted from alveolar macrophages of 6 MWCNT mice and 6 control mice and hybridized to Illumina Mouse WG-6 v2 microarrays. Transcriptional profiling of alveolar immune cells in 15 sarcoidosis patients and 12 healthy humans was previously performed using Affymetrix Human GeneChip U133A 2.0 microarrays. Rigorous statistical methods were used to identify differentially expressed genes. To better elucidate gene expression pathways, integrated network and gene set enrichment analysis (GSEA) were applied. To confirm differential expression of select network genes, we performed qPCR studies using the ABI Prism 7300 Detection. Results: We identified over 1000 genes that were differentially expressed between the control and the MWCNT mice. Gene Ontology functional analysis showed over-representation of processes primarily involved in immunity and inflammation in MCWNT mice. Applying a more comprehensive pathway analysis using GSEA to both mouse and human samples revealed upregulation of 92 gene sets in MWCNT mice and 142 gene sets in sarcoidosis patients. Commonly activated pathways in both MWCNT mice and sarcoidosis included adaptive immunity, T-cell signaling, IL-12/IL-17 signaling and oxidative phosphorylation. Differences in selective gene set enrichment between MWCNT mice and sarcoidosis patients were also observed, among them IL-27 signaling, NK-mediated cytotoxicity and proteasome pathways. We applied network analysis to differentially expressed genes common between the MWCNT model and human sarcoidosis to identify key drivers of disease and putative therapeutic targets. Conclusions: Our MWCNT murine model has an alveolar macrophage signature that varies significantly from control mice. Application of an unbiased transcriptomic approach revealed substantial functional similarities between a murine MWCNT model and human sarcoidosis particularly with respect to activation of immune-specific pathways.

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A novel model of common Toll-like receptor 4- and injury-induced transcriptional themes in human leukocytes.

Publications

A novel model of common Toll-like receptor 4- and injury-induced transcriptional themes in human leukocytes.

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