Transcriptomic analysis of emergency granulopoiesis-generated neutrophils compared to steady state (control) neutrophils
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ABSTRACT:
ORGANISM(S): Danio rerio
PROVIDER: GSE217064 | GEO | 2023/05/01
REPOSITORIES: GEO
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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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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.
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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.
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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.
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Project description:The current model of hematopoiesis only resolves the thymus around the production and establishment of the peripheral T cell pool. However, the role and in situ development of other immune subsets has been overlooked. We aim to demonstrate that during TL1A and IL-18 induced inflammation, the thymus is capable of producing other cell types such as neutrophils, monocytes, and macrophages and that these potentially have other functions aside from supporting T cell development as scavengers. Here we have proven that ex vivo and in vivo treatment with TL1A and IL-18 results in acute thymic atrophy by a massive loss of DP T cells and shrinking of the thymic lobe. By electron microscopy, flow cytometry and single cell we demonstrate that neutrophils are able to maturate inside the thymus lobe in a NOTCH-independent manner. We used fate-mapping tools to elucidate the origin of thymic neutrophils since we observed a great expansion in our culture that is isolated from the influx of BM progenitors. The Rag1-Cre Rosa26-YFP fate mapping model revealed that neutrophils share a common progenitor with T cells, while monocytes/macrophages do not. Furthermore, we found that most of the thymic GMPs (defined as Lin-Sca-1-c-Kit+CD16/32+CD34+) show history of Rag1 expression in comparison with bone marrow GMPs. Additionally, by using Ms4a3-Cre Rosa26Tdtomato fate mapping model we observed that there was not difference in Tdt labeling between the thymus and bone marrow, suggesting that thymic neutrophils still undergo conventional neutrophils pathway arising from GMPs. Moreover, we show that thymic-derived neutrophils are functional and are capable of forming extracellular neutrophils traps (NETs) similarly to benchmark peritoneal neutrophils. We found that the expansion of thymic neutrophils is GM-CSF dependent by using Csf2rb KO mice. Additionally, we identified DR3+ and IL-18Rα+ expressing subsets of ILCs and gdT cells as the cellular source GM-CSF. Lastly, in vivo treatment with TL1A+IL-18 lead to emergency granulopoiesis and an increase of neutrophils in all the organs investigated, including the thymus.
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Project description:RNA-sequencing was performed to look for transcriptional differences between wild-type and Mpc2-deficient granulocyte-macrophage progenitors immediately following the deletion of Mpc2. Paper abstract: Hematopoietic stem and progenitor cells likely engage specific metabolic pathways to promote homeostasis of downstream mature lineages. We examined hematopoiesis in mice conditionally deficient in genes required for long-chain fatty acid oxidation (Cpt2), glutaminolysis (Gls), or mitochondrial pyruvate import (Mpc2). Genetic ablation of Cpt2 or Gls minimally impacted most blood lineages. Deletion of Mpc2 led to a sharp decline in mature myeloid cells and a slower reduction in T cells, whereas other hematopoietic lineages were unaffected. Yet MPC2-deficient monocytes and neutrophils rapidly recovered due to a transient increase in proliferation of myeloid but not other progenitors. Competitive bone marrow chimera and stable isotope tracing experiments demonstrated that this proliferative burst was progenitor-intrinsic and accompanied by a metabolic switch to glutaminolysis. Myeloid recovery after loss of MPC2 or cyclophosphamide treatment was delayed in the absence of GLS. Reciprocally, MPC2 was not required for myeloid recovery after cyclophosphamide treatment. Thus, whereas mitochondrial pyruvate metabolism maintains myelopoiesis under steady-state conditions, rapid recovery from acute loss of myeloid cells requires a switch to glutaminolysis in progenitors.
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Project description:Polymorphonuclear neutrophils are key actors in the pathophysiology of sickle cell disease, but specific factors underlying their activation and sustained inflammation are not well documented. In the present study, we investigated the proteome of neutrophils by a label-free global comparative approach between 4 non-treated sickle patients (SS genotype) at steady state and 4 healthy donors. We identified 101 proteins differentially expressed in SS and normal neutrophils. We found overexpression of CD64 and under-expression of CD62L suggestive of an activated and aged neutrophil profile in SS patients. Comparison of the two proteomes revealed a strong involvement of the type 1 interferon (IFN) response pathway with a 3- to 84-fold increase of type 1 IFN-induced proteins in SS neutrophils, and overexpression of STAT1 and STAT2. Thus, we next determined the plasmatic concentration of type 1 IFNs (IFNα and IFNβ) using the digital-ELISA technology and found a significant higher concentration of IFNα in the plasma from half of our SS patients compared to controls. Overall, a dramatic high-level expression of IFNα signaling proteins in neutrophils from SS patients suggests auto-inflammatory-like phenotype in sickle cell disease at steady state. This finding could open the way to new anti-inflammatory therapies.
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