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Immature neutrophil subsets and emergency granulopoiesis drive sepsis immune suppression and a specific extreme response to infection [WB_ECG]

ABSTRACT: Immature neutrophil subsets and emergency granulopoiesis drive sepsis immune suppression and a specific extreme response to infection [WB_ECG]

PROVIDER: PRJNA891701 | ENA |

REPOSITORIES: ENA

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Immature neutrophil subsets and emergency granulopoiesis drive sepsis immune suppression and a specific extreme response to infection [WB_ECG]

Project description:Sepsis, the dysregulated host response to infection leading to organ dysfunction, arises from diverse mechanisms that are poorly resolved by sepsis as a syndromic classification, confounding immunotherapy trials. Here we delineate neutrophil and granulopoietic disturbances underlying sepsis pathophysiology. We present a whole blood single-cell multiomic sepsis response atlas (272,993 cells, n=39 individuals), revealing multiple immature neutrophil populations that were collectively immunosuppressive, inhibiting CD4+ T cell proliferation and activation in co-culture. We traced this to altered granulopoiesis using single-cell multiomic mapping of circulating hematopoietic stem cells (HSCs) (29,366 cells, n=27). We show how these features are enriched in a subset of patients, resolving a specific poor outcome endotype (sepsis response signature SRS1). SRS1 patients have increased IL1R2+ immature neutrophils, epigenetic signatures of emergency granulopoiesis transcription factors in HSCs, and STAT3 features across infectious disease settings. Our findings delineate an immunohematopoietic axis, therapeutic targets and stratified medicine approach to sepsis.

2024-10-16 | GSE216009 | GEO

Immature neutrophil subsets and emergency granulopoiesis drive sepsis immune suppression and a specific extreme response to infection [HSPC_ECG]

2024-10-16 | GSE216007 | GEO

Immature neutrophil subsets and emergency granulopoiesis drive sepsis immune suppression and a specific extreme response to infection

Project description:Immature neutrophil subsets and emergency granulopoiesis drive sepsis immune suppression and a specific extreme response to infection

| PRJNA891705 | ENA

Immature neutrophil subsets and emergency granulopoiesis drive sepsis immune suppression and a specific extreme response to infection [HSPC_ECG]

Project description:Immature neutrophil subsets and emergency granulopoiesis drive sepsis immune suppression and a specific extreme response to infection [HSPC_ECG]

| PRJNA891700 | ENA

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.

2017-04-04 | E-MTAB-4668 | biostudies-arrayexpress

Transcriptomic analysis of emergency granulopoiesis-generated neutrophils compared to steady state (control) neutrophils

Project description:Functional analysis demonstrates that neutrophils generated by emergency granulopoiesis have elevated bactericidal activity when compared to control (steady state) neutrophils. To determine if transcriptomic changes support these functional adaptations, we performed gene expression analysis on emergency granulopoiesis and steady state neutrophils before and after infection.

2023-05-01 | GSE217064 | GEO

In Fanconi Anemia, impaired accumulation of bone marrow neutrophils during emergency granulopoiesis induces hematopoietic stem cell stress

Project description:Fanconi Anemia (FA) is an inherited disorder of DNA-repair caused by mutation in one of 20+ interrelated genes that repair intra-strand DNA crosslinks and rescue collapsed or stalled replication forks. The most common hematologic abnormality in FA is anemia, but progression to bone marrow failure (BMF), clonal hematopoiesis, or acute myeloid leukemia (AML) may also occur. In prior studies, we found that Fanconi DNA-repair is required for successful emergency granulopoiesis; the process for rapid neutrophil production during the innate immune response. Specifically, Fancc-/- mice did not develop neutrophilia in response to emergency granulopoiesis stimuli, but instead exhibited apoptosis of bone marrow hematopoietic stem cells (HSCs) and differentiating neutrophils. Repeated emergency granulopoiesis challenges induced BMF in most Fancc-/- mice, with AML in survivors. In contrast, we found equivalent emergency granulopoiesis-induced neutrophilia in Fancc-/-Tp53+/- mice and wild type (WT) mice, without BMF in either. Since bone marrow neutrophil accumulation triggers termination of emergency granulopoiesis, we hypothesize neutrophilia protects Fancc-/-Tp53+/- bone marrow from the stress of sustained inflammatory physiology, as experienced by Fancc-/- mice.

2024-08-28 | GSE267161 | GEO

Immature neutrophil subsets and emergency granulopoiesis drive sepsis immune suppression and a specific extreme response to infection

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-10-16 | GSE216011 | GEO

Altered neutrophil and granulopoiesis biology underlie a poor outcome sepsis endotype

Project description:The maladaptive response to infection leading to the clinical syndrome of sepsis is highly heterogeneous, confounding immunotherapy trials. Here we establish the pathophysiology of a sepsis response endotype informative for immune state, disease severity, outcome and therapy. We applied whole blood single-cell multiomics (272,993 cells, n=39 individuals) and found patients with this endotype had increased IL1R2+ immature neutrophils, confirmed using CyTOF (n=41 samples) and RNA-sequencing (n=677 individuals), and upregulated STAT3 programs with plasma cytokine profiles of emergency granulopoiesis (EG). We characterised sepsis hematopoietic stem cells (29,336 cells, n=27 samples) with multiomics, and demonstrated endotype-specific EG transcriptional skewing together with STAT3 and EG master regulator CEBPB epigenetic signatures. Our findings establish an immunohematopoietic basis for a deleterious sepsis endotype and nominate IL-6/G-CSF as potential therapeutic targets.

| EGAS00001006283 | EGA

Age-induced alterations of granulopoiesis generate atypical neutrophils that aggravate stroke pathology. [scRNA-Seq 2]

Project description:Stroke in aging leads to a dysregulated emergency granulopoiesis impacting neurological outcome.

2023-05-16 | GSE231822 | GEO