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Broad transcriptional firing represses bactericidal activity in human airway neutrophils [10hours_transmigrated_CFASN_Neutrophils]

ABSTRACT: In this model, naïve blood neutrophils are migrated through a small airway epithelium grown at air-liquid interface toward CF airway fluid supernatant (CFASN, which corresponds to sputum sequentially centrifuged to remove cells and bacteria) or leukotriene B4 (LTB4, transmigration control), placed apically.

ORGANISM(S): Homo sapiens

PROVIDER: GSE167069 | GEO | 2021/02/19

REPOSITORIES: GEO

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BROAD TRANSCRIPTIONAL FIRING REPRESSES BACTERICIDAL ACTIVITY IN HUMAN AIRWAY NEUTROPHILS

Project description:Neutrophils are often considered terminally differentiated and poised for bacterial killing. In chronic diseases such as cystic fibrosis (CF), an unexplained paradox pits massive neutrophil presence against prolonged bacteria infections. Here, we show that neutrophils recruited to CF airways in vivo and in an in vitro transmigration model display rapid and broad transcriptional firing, leading to an upregulation of survival and anabolic genes, and a downregulation of antimicrobial genes. Newly transcribed RNAs are mirrored by the appearance of corresponding proteins, confirming active translation in these cells. Remarkably, treatment by the RNA polymerase II and III inhibitor alpha-amanitin restored expression of key antimicrobial genes, and increased bactericidal capacity of CF airway neutrophils in vitro and in short-term sputum cultures ex vivo. Broadly, our findings show that neutrophil plasticity is regulated at the terminal organ via RNA and protein synthesis, leading to adaptations that profoundly impact their canonical functions (i.e., bacterial clearance).

2021-01-22 | GSE165265 | GEO

Broad transcriptional firing represses bactericidal activity in human airway neutrophils [Transcriptional_Blockage_CFASN_Neutrophils]

Project description:Neutrophils are often considered terminally differentiated and poised for bacterial killing. In chronic diseases such as cystic fibrosis (CF), an unexplained paradox pits massive neutrophil presence against prolonged bacteria infections. Here, we show that neutrophils recruited to CF airways in vivo and in an in vitro transmigration model display rapid and broad transcriptional firing, leading to an upregulation of survival and anabolic genes, and a downregulation of antimicrobial genes. Newly transcribed RNAs are mirrored by the appearance of corresponding proteins, confirming active translation in these cells. Remarkably, treatment by the RNA polymerase II and III inhibitor Alpha-amanitin restored expression of key antimicrobial genes, and increased bactericidal capacity of CF airway neutrophils in vitro and in short-term sputum cultures ex vivo. Broadly, our findings show that neutrophil plasticity is regulated at the terminal organ via RNA and protein synthesis, leading to adaptations that profoundly impact their canonical functions (i.e., bacterial clearance).

2021-02-19 | GSE167066 | GEO

Spleen vs Leukotriene B4 (LTB4) Treated B cell

Project description:total RNA from mouse (male c57BL/6) spleen labeled with Cy3 vs total RNA from mouse (male c57BL/6) B cells treated with Leukotriene B4 (LTB4) labeled with Cy5- time course with repeats Keywords: ordered

2003-04-14 | GSE390 | GEO

Mus musculus

Project description:Spleen vs Leukotriene B4 (LTB4) Treated B cell

| PRJNA84917 | ENA

Study of Leukotriene B4 (LTB4) effect on primary human monocytes transcription profile

Project description:Leukotriene B4 (LTB4) is a potent lipid mediator of inflammation, implicated in numerous diseases including atherosclerosis. We have used primary human monocytes, which express both receptors, to analyze transcriptional responses to LTB4. Comparisons were made between LTB4- and vehicle-treated samples at the same time point. The analysis showed that expression of 72 genes was upregulated at least two-fold at two time points. These genes include multiple chemokines as well as some genes with unknown function. Keywords: time course

2007-10-18 | GSE9332 | GEO

Effects of BLT1 inhibition in a mouse model of liver fibrosis

Project description:Nonalcoholic steatohepatitis (NASH) is a prevalent disease that can ultimately progress to more severe forms of disease including liver fibrosis, cirrhosis, hepatocellular carcinoma (HCC), and ultimately death. A key feature of NASH is lobular inflammation, which is a major driver of disease progression, and both innate and adaptive immune mechanisms support and perpetuate hepatic inflammation in NASH. Previous studies have demonstrated that the pro-inflammatory leukotriene B4 (LTB4) is a potent chemoattractant that drives macrophage and neutrophil chemotaxis, and genetic loss or inhibition of its high affinity receptor, leukotriene B4 receptor 1 (BLT1), results in improved insulin sensitivity and decreased lipid accumulation in the liver. Accordingly, the LTB4-BLT1 axis is a potential therapeutic target for the treatment of liver steatosis and insulin resistance by modulating inflammation.The goal of this study is to validate the therapeutic efficacy of BLT1 inhibition in a NASH mouse model.

2023-11-25 | GSE248273 | GEO

Homo sapiens

Project description:Study of Leukotriene B4 (LTB4) effect on primary human monocytes transcription profile

| PRJNA103009 | ENA

Identification of genes effected by GM-CSF treatment in mature human neutrophils

Project description:The objective of this study was to compare the transcriptional repertoire of mature human neutrophils before and after GM-CSF treatment by using oligonucleotide microarrays. Leukotriene B4 (LTB4) is an important pro-inflammatory lipid mediator generated by neutrophils upon activation. Granulocyte/macrophage colony-stimulating factor (GM-CSF) stimulation is known to enhance agonist-mediated LTB4 production of neutrophils within minutes, a process called “priming”. Here, we demonstrate that GM-CSF also limits the production of LTB4 by neutrophils via a transcriptional mechanism at later time points. We identified hematopoietic specific Ras homologous (RhoH)/translocation three four (TTF), which was induced following GM-CSF stimulation in neutrophils, as a key regulator in this process. Neutrophils derived from RhoH/TTF-deficient (Rhoh-/-) mice demonstrated increased LTB4 production upon activation compared with normal mouse neutrophils. Moreover, neutrophils from cystic fibrosis patients expressed enhanced levels of RhoH/TTF and generated less LTB4 upon activation compared with normal human neutrophils. Taken together, these data suggest that RhoH/TTF represents an inducible feedback inhibitor in neutrophils that is involved in the limitation of innate immune responses.

2009-03-31 | GSE15139 | GEO

Cancer-produced metabolites of 5-lipoxygenase induce tumor-evoked Bregs via peroxisome proliferator-activated receptor alpha

Project description:Breast cancer cells facilitate distant metastasis through the induction of immunosuppressive regulatory B cells, designated tBregs. We report here that, to do this, breast cancer cells produce metabolites of the 5-lipoxygenase (5-LO) pathway such as leukotriene B4 (LTB4) to activate the proliferator-activated receptor alpha (PPARalpha) in B cells. Inactivation of LTB4 signaling or genetic deficiency of PPARalpha in B cells blocks the generation of tBregs and thereby abrogates lung metastasis in mice with established breast cancer. Thus, in addition to eliciting fatty acid oxidation and metabolic signals, PPARalpha initiates programs required for differentiation of tBregs. We propose that PPARalpha in B cells or/and tumor 5-LO pathways represents new targets for pharmacological control of tBreg-mediated cancer escape.

2013-03-13 | GSE43278 | GEO

Transcription profiling of human monocytic cell line MonoMac 6 after stimulation with pro- abd anti-inflammatory eicosanoids

Project description:Eicosanoids are potent regulators of gene expression of inflammatory cells. Pro- (leukotrienes B4 and C4) and anti-indflammatory (lipoxins A4 and B4) eicosanoids have been described in the literature but the detailed impact of these lipid mediators on the gene expression pattern of monocytic cells has not been studied in detail. We cultured the permanent monocytic cell line MonoMac 6 for 12 h in the absence (solvent control) and presence of these eicosanoids and quantified the differential gene expression patterns using the microarray technology. Experiment Overall Design: MonoMac6 cells were grown according to the recommendations of the German Tissue and Cell Culture Collection (Braunschweig) to near confluency. Then 100 nM of the eicosanoids (leukotriene B4, leukotriene C4, lipoxin A4, lipoxin B4) were added to the culture medium as DMSO stock solution and the cells were further cultured for 12 h with the stimuli. Then the cells were harvested, washed and total RNA was extracted according to the Qiagen protocol. Total RNA was used for microarray hybridization.

2008-10-20 | E-GEOD-8928 | biostudies-arrayexpress

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