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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

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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

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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.

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Aspergillus fumigatus-derived gliotoxin impairs innate immune cell activation through modulating lipid mediator production in macrophages

Project description:Gliotoxin (GT), a major secondary metabolite and virulence factor of Aspergillus fumigatus, suppresses innate immunity and supports the evasion of host immune responses. Recently, we revealed that GT blocks leukotriene (LT)B4 formation by directly inhibiting LTA4 hydrolase (LTA4H) in activated human neutrophils and monocytes. Here, we elucidated the impact of GT on LTB4 biosynthesis and the complex lipid mediator network in human M1- and M2-like monocyte-derived macrophage (MDM) subtypes and studied the respective consequences for innate immune cell functions. Notably, in resting MDMs, GT elicited prostaglandin and 12/15-lipoxygenase product formation, although less efficient than bacterial exotoxins. In activated MDM, LTB4 formation was effectively suppressed by GT, connected to impaired macrophage phagocytic activity, and detrimental consequences for neutrophil movement and migration. Conclusively, GT impairs functions of activated innate immune cells through suppression of LTB4 formation, while GT may prime the immune system by provoking prostaglandin formation and 12/15-lipoxygenase-derived LM.

2024-11-13 | PXD045819 | Pride

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

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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

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