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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE216011 | GEO | 2024/10/16

REPOSITORIES: GEO

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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 [WB_ECG]

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

| PRJNA891701 | 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

Neutrophils and emergency granulopoiesis drive immune suppression and an extreme response endotype during sepsis DAC

Project description:Data Access Committee EGAC00001003275

| EGAC00001003275 | EGA

BCG vaccination-induced emergency granulopoiesis provides rapid protection from neonatal sepsis.

Project description:Death from sepsis in the neonatal period remains a serious threat for millions. Within 3 days of administration, bacille Calmette-Guérin (BCG) vaccination can reduce mortality from neonatal sepsis in human newborns, but the underlying mechanism for this rapid protection is unknown. We found that BCG was also protective in a mouse model of neonatal polymicrobial sepsis, where it induced granulocyte colony-stimulating factor (G-CSF) within hours of administration. This was necessary and sufficient to drive emergency granulopoiesis (EG), resulting in a marked increase in neutrophils. This increase in neutrophils was directly and quantitatively responsible for protection from sepsis. Rapid induction of EG after BCG administration also occurred in three independent cohorts of human neonates.

| S-EPMC8008103 | biostudies-literature

Differential expression of granulopoiesis related genes in neutrophil subsets distinguished by membrane expression of CD177.

Project description:ObjectiveDifferential gene expression in CD177+ and CD177- neutrophils was investigated, in order to detect possible differences in neutrophil function which could be related to the pathogenesis of ANCA-associated Vasculitides (AAV).MethodsNeutrophils were isolated from healthy controls (HC) with high, negative or bimodal CD177 expression, and sorted into CD177+ and CD177- subpopulations. Total RNA was screened for expression of 24,000 probes with Illumina Ref-8 Beadchips. Genes showing differential expression between CD177+ and CD177- subsets in microarray analysis were re-assessed using quantitative-PCR. CD177 expression on neutrophil precursors in bone marrow was analyzed using quantitative PCR and flowcytometry.ResultsThe proportion of CD177+ cells increased during neutrophil maturation in bone marrow. Fold change analysis of gene expression profile of sorted CD177+ and CD177- neutrophils resulted in 14 genes with fold change (fc) >3 difference in expression. Interestingly, 10 of these genes have been reported to change significantly in expression during neutrophil maturation, and most of these genes were granule protein (GP) coding genes. mRNA expression levels measured by RT-PCR of a number of these GP, and of PR3 and MPO were higher in the CD177- neutrophil subset in HC, however, particular granule protein amounts were comparable between CD177+ and CD177- neutrophil subsets. AAV patients had higher amounts of CD177+ neutrophils, but contrary to neutrophils from HC expression of GP-genes was increased, possibly due to activation.ConclusionThe neutrophil population can be distinguished by membrane expression of CD177 into subsets that are different in expression of GP mRNA but not in GP protein production. GP gene expression is also elevated in AAV patients, which is not explained by skewed distribution of CD177+ and CD177- subsets but may be associated with neutrophil activation during on-going inflammation.

| S-EPMC4057222 | biostudies-literature

Emergency granulopoiesis promotes neutrophil-dendritic cell encounters that prevent mouse lung allograft acceptance.

Project description:The mechanisms by which innate immune signals regulate alloimmune responses remain poorly understood. In the present study, we show by intravital 2-photon microscopy direct interactions between graft-infiltrating neutrophils and donor CD11c(+) dendritic cells (DCs) within orthotopic lung allografts immediately after reperfusion. Neutrophils isolated from the airways of lung transplantation recipients stimulate donor DCs in a contact-dependent fashion to augment their production of IL-12 and expand alloantigen-specific IFN-γ(+) T cells. DC IL-12 expression is largely regulated by degranulation and induced by TNF-α associated with the neutrophil plasma membrane. Extended cold ischemic graft storage enhances G-CSF-mediated granulopoiesis and neutrophil graft infiltration, resulting in exacerbation of ischemia-reperfusion injury after lung transplantation. Ischemia reperfusion injury prevents immunosuppression-mediated acceptance of mouse lung allografts unless G-CSF-mediated granulopoiesis is inhibited. Our findings identify granulopoiesis-mediated augmentation of alloimmunity as a novel link between innate and adaptive immune responses after organ transplantation.

| S-EPMC3234670 | biostudies-literature

Augmenting emergency granulopoiesis with CpG conditioned mesenchymal stromal cells in murine neutropenic sepsis.

Project description:Patients with immune deficiencies from cancers and associated treatments represent a growing population within the intensive care unit with increased risk of morbidity and mortality from sepsis. Mesenchymal stromal cells (MSCs) are an integral part of the hematopoietic niche and express toll-like receptors, making them candidate cells to sense and translate pathogenic signals into an innate immune response. In this study, we demonstrate that MSCs administered therapeutically in a murine model of radiation-associated neutropenia have dual actions to confer a survival benefit in Pseudomonas aeruginosa pneumo-sepsis that is not from improved bacterial clearance. First, MSCs augment the neutrophil response to infection, an effect that is enhanced when MSCs are preconditioned with CpG oligodeoxynucleotide, a toll-like receptor 9 agonist. Using cytometry by time of flight, we identified proliferating neutrophils (Ly6GlowKi-67+) as the main expanded cell population within the bone marrow. Further analysis revealed that CpG-MSCs expand a lineage restricted progenitor population (Lin-Sca1+C-kit+CD150-CD48+) in the bone marrow, which corresponded to a doubling in the myeloid proliferation and differentiation potential in response to infection compared with control. Despite increased neutrophils, no reduction in organ bacterial count was observed between experimental groups. However, the second effect exerted by CpG-MSCs is to attenuate organ damage, particularly in the lungs. Neutrophils obtained from irradiated mice and cocultured with CpG-MSCs had decreased neutrophil extracellular trap formation, which was associated with decreased citrullinated H3 staining in the lungs of mice given CpG-MSCs in vivo. Thus, this preclinical study provides evidence for the therapeutic potential of MSCs in neutropenic sepsis.

| S-EPMC7556132 | biostudies-literature

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