Dataset Information

Transcriptome profiling of primary murine monocytes, lung macrophages and lung dendritic cells reveals a distinct expression of genes involved in cell trafficking.

ABSTRACT: BACKGROUND: Peripheral blood monocytes (PBMo) originate from the bone marrow, circulate in the blood and emigrate into various organs where they differentiate into tissue resident cellular phenotypes of the mononuclear phagocyte system, including macrophages (Mphi) and dendritic cells (DC). Like in other organs, this emigration and differentiation process is essential to replenish the mononuclear phagocyte pool in the lung under both inflammatory and non-inflammatory steady-state conditions. While many studies have addressed inflammation-driven monocyte trafficking to the lung, the emigration and pulmonary differentiation of PBMo under non-inflammatory conditions is much less understood. METHODS: In order to assess the transcriptional profile of circulating and lung resident mononuclear phagocyte phenotypes, PBMo, lung Mphi and lung DC from naïve mice were flow-sorted to high purity, and their gene expression was compared by DNA microarrays on a genome-wide scale. Differential regulation of selected genes was validated by quantitative PCR and on protein level by flow cytometry. RESULTS: Differentially-expressed genes related to cell traffic were selected and grouped into the clusters (i) matrix metallopeptidases, (ii) chemokines/chemokine receptors, and (iii) integrins. Expression profiles of clustered genes were further assessed at the mRNA and protein levels in subsets of circulating PBMo (GR1- vs GR1+) and lung resident macrophages (alveolar vs interstitial Mphi). Our data identify differentially activated genetic programs in circulating monocytes and their lung descendents. Lung DC activate an extremely diverse set of gene families but largely preserve a mobile cell profile with high expression levels of integrin and chemokine/chemokine receptors. In contrast, interstitial and even more pronounced alveolar Mphi, stepwise downregulate gene expression of these traffic relevant communication molecules, but strongly upregulate a distinct set of matrix metallopetidases potentially involved in tissue invasion and remodeling. CONCLUSION: Our data provide new insight in the changes of the genetic profiles of PBMo and their lung descendents, namely DC and Mphi under non-inflammatory, steady-state conditions. These findings will help to better understand the complex relations within the mononuclear phagocyte pool of the lung.

SUBMITTER: Zaslona Z

PROVIDER: S-EPMC2639356 | biostudies-literature | 2009

REPOSITORIES: biostudies-literature

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Transcriptome profiling of primary murine monocytes, lung macrophages and lung dendritic cells reveals a distinct expression of genes involved in cell trafficking.

Zasłona Zbigniew Z Wilhelm Jochen J Cakarova Lidija L Marsh Leigh M LM Seeger Werner W Lohmeyer Jürgen J von Wulffen Werner W

Respiratory research 20090116

<h4>Background</h4>Peripheral blood monocytes (PBMo) originate from the bone marrow, circulate in the blood and emigrate into various organs where they differentiate into tissue resident cellular phenotypes of the mononuclear phagocyte system, including macrophages (Mphi) and dendritic cells (DC). Like in other organs, this emigration and differentiation process is essential to replenish the mononuclear phagocyte pool in the lung under both inflammatory and non-inflammatory steady-state conditio ...[more]

PMID: 19149869

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Project description:Macrophages are mononuclear phagocytes that constitute a first line of defense against pathogens. While lethal to many microbes, they are the primary host cells of Leishmania spp. parasites, the obligate intracellular pathogens that cause leishmaniasis. We conducted transcriptomic profiling of two Leishmania species and the human macrophage over the course of intracellular infection by using high-throughput RNA sequencing to characterize the global gene expression changes and reprogramming events that underlie the interactions between the pathogen and its host. A systematic exclusion of the generic effects of large-particle phagocytosis revealed a vigorous, parasite-specific response of the human macrophage early in the infection that was greatly tempered at later time points. An analogous temporal expression pattern was observed with the parasite, suggesting that much of the reprogramming that occurs as parasites transform into intracellular forms generally stabilizes shortly after entry. Following that, the parasite establishes an intracellular niche within macrophages, with minimal communication between the parasite and the host cell later during the infection. No significant difference was observed between parasite species transcriptomes or in the transcriptional response of macrophages infected with each species. Our comparative analysis of gene expression changes that occur as mouse and human macrophages are infected by Leishmania spp. points toward a general signature of the Leishmania-macrophage infectome. Little is known about the transcriptional changes that occur within mammalian cells harboring intracellular pathogens. This study characterizes the gene expression signatures of Leishmania spp. parasites and the coordinated response of infected human macrophages as the pathogen enters and persists within them. After accounting for the generic effects of large-particle phagocytosis, we observed a parasite-specific response of the human macrophages early in infection that was reduced at later time points. A similar expression pattern was observed in the parasites. Our analyses provide specific insights into the interplay between human macrophages and Leishmania parasites and constitute an important general resource for the study of how pathogens evade host defenses and modulate the functions of the cell to survive intracellularly.

Project description:Trafficking of monocytes into lung tissue and their differentiation into lung resident macrophages and dendritic cells is supposed to be regulated by the expression of specific gene clusters, which promote cell-cell interaction, migration and matrix degradation and the acquisition of tissue specific cellular phenotypes. Traffic related gene clusters include chemokines, integrins, and tissue-degrading matrix metallopeptidases, for all of which members have been shown to be functionally important. A complete picture, however, of the gene clusters that are regulated during in vivo migration and differentiation of peripheral blood monocytes under non-inflammatory conditions has not been obtained yet. Currently, adaptive changes of cellular phenotypes cannot be directly assessed by cell fate mapping during the slow trafficking of mononuclear phagocytes to lung tissue under steady-state conditions. Therefore, as an alternative approach to gain a better insight into the genetic programs that drive the mononuclear phagocyte migration and differentiation processes, the transcriptomes of circulating monocytes were compared with their lung tissue mononuclear phagocyte progeny. Experiment Overall Design: A total of 32 animals were used in this study. From each Animal, Monocytes, Macrophages and dendritic cells were isolated. Cells were sorted from blood-free lungs and peripheral blood. In order to get enough RNA for a labeling reaction, RNA of each 4 of these animals was pooled (same amount of RNA per animal). The different pools were subjected to microarray analysis comparing Monocytes, Macrophages and Dendritic Cells in a ring design with 4 hybridizations per comparison. There were 8 different pools per cell type, 4 of which were labeled with Cy3 and the other 4 were labelled with Cy5 (balanced dye-swap). Each possible combination of cell types was compared with 4 hybridizations, resulting in a total number of 12 hybridizations. Each hybridization used RNA from different animals. In each of these comparisons, each cell type was labelled twice with Cy3 and twice with Cy5.

Dataset Information

Transcriptome profiling of primary murine monocytes, lung macrophages and lung dendritic cells reveals a distinct expression of genes involved in cell trafficking.

Publications

Transcriptome profiling of primary murine monocytes, lung macrophages and lung dendritic cells reveals a distinct expression of genes involved in cell trafficking.

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