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Expression analysis of altered neutrophils from septic mice

ABSTRACT: Neutrophils are critical for effective anti-fungal immune responses. However, in fungal sepsis neutrophils undergo a phenotypical (Ly6G downregulation) and functional alteration (defective ROS production), impairing their anti-fungal capacity. Therefore we wish to characterize the neutrophils in septic mice transcriptionally to describe their role in driving sepsis. We included several control groups. Mice that lack T cells (TCRaKO mice) have increased resistance to the infection and their neutrophils appear unaltered. We identified G-CSF and DNA/histones to be responsible for affecting granulopoiesis, as rG-CSF and Clodronate liposomes combined expand Ly6Glow neutrohils in naive mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE160301 | GEO | 2021/10/01

REPOSITORIES: GEO

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Human sepsis with plasma samples

Project description:The project examines the mechanisms of neutrophil dysfunction during sepsis. Our work uncovered the central role of cell free circulating histones in eliminating mature neutrophil in favour of immature cells and characterized the mechanisms that regulate their release following systemic infection. Mature and immature neutrophil Ly6Ghigh and Ly6Glow populations isolated from the spleens of WT and TCRα-deficient mice either naïve or infected with C. albicans were characterized. In addition, these populations were compared to neutrophils isolated from WT mice receiving Clodronate-liposomes and recombinant G-CSF. These studies demonstrated that T-cell derived histones drive the release of G-CSF in the spleen and progressively eliminate mature neutrophils by shortening their lifespan. Finally, we conducted proteomic analysis of plasmas isolated from patients with microbial sepsis to correlate markers of neutrophil death to plasma cytokine and histone levels, confirming the pathogenic role these molecules play during sepsis in humans.

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Changes in gene expression during G-CSF-induced emergency granulopoiesis in humans

Project description:Emergency granulopoiesis refers to the increased production of neutrophils in bone marrow and their release into circulation induced by severe infection. Several studies point to a critical role for granulocyte colony-stimulating factor (G-CSF) as the main mediator of emergency granulopoiesis. However, the consequences of G-CSF stimulation on the transcriptome of neutrophils and their precursors have not yet been investigated in humans. Here, we examine the changes in mRNA expression induced by administration of G-CSF in vivo, as a model of emergency granulopoiesis in humans. Blood samples were collected from healthy individuals after five days of G-CSF administration. Neutrophil precursors were sorted into discrete stages of maturation by flow cytometry, and RNA was subjected to microarray analysis. mRNA levels were compared to previously published expression levels in corresponding populations of neutrophil precursors isolated from bone marrow of untreated, healthy individuals. 1110 mRNAs were differentially expressed more than 2-fold throughout terminal granulopoiesis. Major changes were seen in pathways involved in apoptosis, cytokine signaling, and Toll-like receptor pathways. In addition, G-CSF treatment reduced the levels of four out of five measured granule proteins in mature neutrophils including the proantibacterial protein hCAP-18, which was completely deficient in neutrophils from G-CSF-treated donors. These results indicate that multiple biological processes are altered in order to satisfy the increased demand for neutrophils during G-CSF-induced emergency granulopoiesis in humans.

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Microarray Experiments for mice lacking or with the Stat5a and 5b genes in blood cells that were treated w/o CMP

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Microarray Experiments for mice lacking or with the Stat5a and 5b genes in blood cells that were treated w/o CMP

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

Project description: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.

2022-09-05 | GSE198154 | GEO

Transcription profiling of mouse wild type and Stat5a or 5b knock-out blood cells treated with GM-CSF to induce granulopoiesis

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2021-01-29 | GSE165743 | GEO

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Physical activity modulates macrophage phenotype in mammary tissue and inhibits tumor progression

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2020-05-15 | GSE150620 | GEO

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