Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Lung neutrophil subsets transcriptomes in WT and CGD mouse in response to fungal PAMPs stimulation

ABSTRACT: The leukocyte NADPH oxidase 2 (NOX2) regulates inflammation independent of its anti-microbial activity. Inherited defects in NOX2 lead to chronic granulomatous disease (CGD), associated with recurrent bacterial and fungal infections, often with excessive neutrophilic inflammation that results in significant inflammatory burden and tissue damage. We previously showed that excessive leukotriene B4 production by NOX2-deficient mouse neutrophils was a key driver of elevated lung neutrophil infiltration in the initial response to pulmonary challenge with the fungal particle zymosan (Song et al Blood 135, 891-903). We now identify IL-1β and downstream G-CSF as additional amplifying signals that augment and sustain neutrophil accrual in CGD mice. Neutrophils, delivered into the lung via LTB4, were the primary source of IL-1β within the airways, and their increased numbers in CGD lungs led to significantly elevated local and plasma G-CSF. Elevated G-CSF simultaneously promoted increased granulopoiesis and mobilized the release of higher numbers of an immature CD101neg neutrophil subset from the marrow, which trafficked to the lung and acquired a significantly more pro-inflammatory transcriptome in CGD mice compared to WT mice. Thus, neutrophil-produced IL-1β in the acute response to fungal cell walls acts sequentially but non-redundantly with LTB4 to deploy neutrophils and amplify inflammation in CGD mice. This illustrates how NOX2 plays a critical role in dampening multiple components of a feed-forward pipeline for neutrophil recruitment, and highlights NOX2 as a key regulator of neutrophil number and function at inflamed sites.

ORGANISM(S): Mus musculus

PROVIDER: GSE198154 | GEO | 2022/09/05

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

RNA-seq of BM neutrophils after treated with IL1b/IL6/PGE2

Project description:To investigate the effects of IL-1β/IL-6/PGE2 on neutrophil modulation, we performed RNA-seq to compare IL-1β/IL-6/PGE2-treated neutrophils to vehicle-treated neutrophils.

2022-12-12 | E-MTAB-12367 | biostudies-arrayexpress

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

Transcriptome kinetics of circulating neutrophils during human experimental endotoxemia

Project description:Polymorphonuclear cells (neutrophils) play an important role in the systemic inflammatory response syndrome and the development of sepsis. These cells are essential for the defense against microorganisms, but may also cause tissue damage. Therefore, neutrophil numbers and activity are considered to be tightly regulated. Previous studies have investigated gene transcription during experimental endotoxemia in whole blood and peripheral blood mononuclear cells. However, the gene transcription response of the circulating pool of neutrophils to systemic inflammatory stimulation in vivo is currently unclear. We examined neutrophil gene transcription kinetics in healthy human subjects (n=4) administered a single dose of endotoxin (LPS, 2 ng/kg iv). In addition, freshly isolated neutrophils were stimulated ex vivo with LPS, TNFα, G-CSF and GM-CSF to identify stimulus-specific gene transcription responses. Whole transcriptome microarray analysis of circulating neutrophils at 2, 4 and 6 hours after LPS infusion revealed activation of inflammatory networks which are involved in signaling of TNFα and IL-1α and IL-1β. The transcriptome profile of inflammatory activated neutrophils in vivo reflects extended survival and regulation of inflammatory responses. We show that these changes in neutrophil transcriptome are most likely due to a combination of early activation of circulating neutrophils by TNFα and G-CSF and a mobilization of young neutrophils from the bone marrow.

2012-06-05 | GSE35590 | GEO

Interferon-gamma Induced Gene Expression Changes in Human Neutrophils

Project description:The cytokine interferon-gamma (IFN-gamma) is used as a drug to treat Chronic Granulomatous Disease (CGD), a group of genetic disorders characterized by defects in components of the neutrophil-resident NADPH oxidase/Nox2 enzyme system. Administration of IFN-gamma to these patients results in decreased incidents of severe infection, but has no effect on the characteristic defect of CGD, the inability to convert oxygen to microbicidal reactive oxygen species. To determine the mechanism by which IFN-gamma enhances the host protective properties of neutrophils, we administered INF-gamma to 10 healthy adult volunteers and carried out transcription profiling by array for neutrophils isolated from their peripheral blood. IFN-gamma was administered to each subject at 4 doses (10, 25, 50 and 100 micrograms/meter squared) with washout periods between each dose. Gene expression levels in neutrophils were measure just before (time 0) and at various times (4, 8, 12, 24, 36, 48, 72 and 96 hours) after administration of IFN-gamma. In the list of samples, individual patients are indicated by 01-10, the dose by D10, D25, D50 and D100, referring to 10, 25, 50 and 100 micrograms / meter squared respectively and the times by visit (V) numbers where VI, V2, V3, V4, V5, V6, V7, V8 and V9 refer to the 0 4, 8, 12, 24, 36, 48, 72 and 96 hour time points respectively.

2018-12-14 | E-MTAB-7261 | biostudies-arrayexpress

Analysis of resident peritoneal macrophage's transcriptome in WT and CGD mice

Project description:The leukocyte NADPH oxidase 2 (NOX2) plays a key role in pathogen killing and immunoregulation. Genetic defects in NOX2 result in chronic granulomatous disease (CGD), associated with microbial infections and inflammatory disorders, often involving the lung. Alveolar macrophages (AM) are the predominant immune cell in the airways at steady state, and limiting their activation is important given constant exposure to inhaled materials, yet the importance of NOX2 in this process is not well-understood. Here, we show a previously undescribed role for NOX2 in maintaining lung homeostasis by suppressing AM activation, as studied using CGD mice or mice with selective loss of NOX2 primarily in macrophages. AM lacking NOX2 have increased cytokine responses to TLR2 and TLR4 stimulation ex vivo. Moreover, between 4 and 12 weeks of age, mice with global NOX2 deletion developed an activated CD11bhigh subset of AM with epigenetic and transcriptional profiles reflecting immune activation compared to WT AM. The presence of CD11bhigh AM in CGD mice correlated with increased numbers of alveolar neutrophils and proinflammatory cytokines at steady state as well as increased lung inflammation following insults. Moreover, deletion of NOX2 primarily in macrophages was sufficient for mice to develop an activated CD11bhigh AM subset and accompanying pro-inflammatory sequela. Additionally, we showed that the altered resident macrophage transcriptional profile in the absence of NOX2 is tissue-specific as these changes were not seen in resident peritoneal macrophages. Thus, these data demonstrate that absence of NOX2 in alveolar macrophages leads to their pro-inflammatory remodeling and dysregulates alveolar homeostasis.

2022-04-03 | GSE198771 | GEO

Bronchoalveolar lavage alveolar macrophage subset transcriptomes in WT and NOX2-knockout mice

2022-04-03 | GSE198769 | GEO

Genome-wide epigenome mapping in alveolar macrophages (CD45+ Siclec F+ CD11c+) from WT (4wks and 12 wks) and CGD (4wks and 12 wks) mice

2022-04-03 | GSE198768 | GEO

Interferon-gamma 1b-Induced Gene Expression Alters Neutrophil Function in Patients with Chronic Granulomatous Disease

Project description:IFNG decreases incidence of infections in chronic granulomatous disease (CGD) without affecting inability of CGD neutrophils to generate essential microbicidal oxidants. Neutrophil (PMN) function, gene expression, and biochemical parameters were measured off IFN-γ and 10-12 hours after 1st and 4th doses of IFN-γ administered to nine CGD patients. Non-directed motility and bactericidal activity were increased after treatment with IFN-γ; ingestion and O2- generation remained unchanged. Treatment decreased expression of 483 genes and increased 386. Genes (11) associated with PMN activity were upregulated. Genes not routinely associated with neutrophil function were increased including MHCI and II, guanylate binding proteins, and an enzyme synthesizing a NOS cofactor. CD11b expression, f-Actin assembly, and CD 274 antigen were increased after treatment as was NO in PMN lysates. NETs formation after ingestion was increased off IFN- but moved toward normal after administration. IFN- provides neutrophils with strategies to compensate for the deficiency found in CGD.

2024-07-01 | E-MTAB-13674 | biostudies-arrayexpress

BTK drives neutrophil activation for sterilizing antifungal immunity

Project description:We describe a previously unappreciated role for Bruton's tyrosine kinase (BTK) in fungal immune surveillance against aspergillosis, an unforeseen complication of BTK inhibitors (BTKi) used for treating B-cell lymphoid malignancies. We studied BTK-dependent fungal responses in neutrophils from diverse populations, including healthy donors, BTKi-treated patients, and X-linked agammaglobulinemia patients. Upon fungal exposure, BTK was activated in human neutrophils in a TLR2-, Dectin-1-, and FcgR-dependent manner, triggering the oxidative burst. BTK inhibition selectively impeded neutrophil-mediated damage to Aspergillus hyphae, primary granule release, and the fungus-induced oxidative burst by abrogating NADPH oxidase subunit p40phox and GTPase RAC2 activation. Moreover, neutrophil-specific Btk deletion in mice enhanced aspergillosis susceptibility by impairing neutrophil function, not recruitment nor lifespan. Conversely, GM-CSF partially mitigated these deficits by enhancing p47phox activation. Our findings underline the crucial role of BTK signaling in neutrophils for antifungal immunity and provide a rationale for GM-CSF use to offset these deficits in susceptible patients.

2024-05-17 | GSE243974 | GEO

Transcriptome kinetics of circulating neutrophils during human experimental endotoxemia

Project description:Polymorphonuclear cells (neutrophils) play an important role in the systemic inflammatory response syndrome and the development of sepsis. These cells are essential for the defense against microorganisms, but may also cause tissue damage. Therefore, neutrophil numbers and activity are considered to be tightly regulated. Previous studies have investigated gene transcription during experimental endotoxemia in whole blood and peripheral blood mononuclear cells. However, the gene transcription response of the circulating pool of neutrophils to systemic inflammatory stimulation in vivo is currently unclear. We examined neutrophil gene transcription kinetics in healthy human subjects (n=4) administered a single dose of endotoxin (LPS, 2 ng/kg iv). In addition, freshly isolated neutrophils were stimulated ex vivo with LPS, TNFM-NM-1, G-CSF and GM-CSF to identify stimulus-specific gene transcription responses. Whole transcriptome microarray analysis of circulating neutrophils at 2, 4 and 6 hours after LPS infusion revealed activation of inflammatory networks which are involved in signaling of TNFM-NM-1 and IL-1M-NM-1 and IL-1M-NM-2. The transcriptome profile of inflammatory activated neutrophils in vivo reflects extended survival and regulation of inflammatory responses. We show that these changes in neutrophil transcriptome are most likely due to a combination of early activation of circulating neutrophils by TNFM-NM-1 and G-CSF and a mobilization of young neutrophils from the bone marrow. After LPS infusion blood was taken at t=0, t=2, t=4 and t=6 hours. Neutrophils were isolated and gene expression of these cells was assessed. T=2, t=4 and t=6 were related to t=0 as control condition

2012-06-04 | E-GEOD-35590 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data