Differential gene expression of neutrophils that lack lymphotoxin beta receptor identifies a metabolic gene signature
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE150243 | GEO | 2020/08/01
REPOSITORIES: GEO
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Project description:Differential gene expression of neutrophils that lack lymphotoxin beta receptor identifies a metabolic gene signature
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Project description:Acute lymphoblastic and myeloblastic leukemias (ALL and AML) have been known to modify the bone marrow microenvironment and disrupt non-malignant hematopoiesis. However, the molecular mechanisms driving these alterations remain poorly defined. Here we show that leukemic cells turn-off lymphopoiesis and erythropoiesis shortly after colonizing the bone marrow. ALL and AML cells express lymphotoxin-a1b2 and activate LTbR signaling in mesenchymal stem cells (MSCs), which turns off IL7 production and prevents non-malignant lymphopoiesis. Genetic or pharmacologic disruption of LTbR signaling in MSCs restores lymphopoiesis but not erythropoiesis, reduces leukemic cell growth, and extends survival of transplant recipients significantly. These studies demonstrate that acute leukemias exploit physiological mechanisms governing hematopoietic output as a strategy for gaining competitive advantage. Our studies also reveal that disrupting the cross-talk between leukemia cells and bone marrow niche cells, and specifically the LTbR pathway, offers new therapeutic opportunities.
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Project description:Neutrophils play a key role in the control of metastatic progression. Neutrophils are phenotypically heterogeneous and can exert either anti- or pro-metastatic functions. Here, we demonstrate that tumor cells capable of forming liver metastases induce an accumulation of neutrophils in the peripheral blood and liver parenchyma. Cancer cell-derived G-CSF, in concert with other factors, mobilizes immature low-density neutrophils that promote liver metastasis. In contrast, mature high-density neutrophils inhibit the formation of liver metastases. Transcriptomic and metabolomic analyses of high- and low- density neutrophils reveal engagement of numerous metabolic pathways specifically in low-density neutrophils. Low-density neutrophils exhibit enhanced global bioenergetic capacity, through their ability to engage mitochondrial-dependent ATP production, and remain capable of executing pro-metastatic neutrophil functions, including NETosis, under nutrient-deprived conditions. Together, these data reveal that distinct pro-metastatic neutrophil populations exhibit a high degree of metabolic flexibility, which facilitates metastatic progression and the formation of liver metastases.
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Project description:[Background] TNFa-induced adipose-related protein (TIARP) is a six-transmembrane protein that is expressed on macrophages, neutrophils and synoviocytes. We have recently reported that TIARP deficient mice (TIARP-/-) spontaneously developed arthritis, and had the high susceptibility to collagen-induced arthritis (CIA) with enhanced interleukin (IL)-6 production. However, the effect of TIARP to neutrophils and fibroblast-like syonoviocytes (FLS) has not been clearly elucidated. [Methods] We analyzed the roles of TIARP in K/BxN serum transfer model using TIARP-/- mice. We characterized the differences of neutrophils between WT and TIARP-/- mice by DNA microarray. Transmigration assays of TIARP-/- neutrophils were performed in vitro and in vivo. FLS were cultured with TNF? and the production of CXCL2 (a specific ligand of CXCR1 and CXCR2) and IL-6 were measured by ELISA. Moreover, TIARP-/- mice transferred with K/BxN serum were treated with anti-IL-6R antibodies. [Results] Arthritis in TIARP-/- mice transferred with K/BxN serum was significantly exacerbated. We identified overexpression of CXCR1 and CXCR2 in TIARP-/- neutrophils by DNA microarray. Neutrophils from TIARP-/- mice showed strong migration activity. The enhancement of chomotactic activity of TIARP-/- neutrophil was greatly facilitated by CXCL2 in vitro and in vivo. In addition, TIARP-/-FLS has enhanced the production of CXCL2 and IL-6 and the cell proliferation in the presence of TNFa, and the blockade of IL-6R significantly attenuated arthritis in vivo. [Conclusion] Our findings indicate that TIARP might down-regulate the production of CXCL2 and IL-6 in FLS, and the expression of chemokine receptors (CXCR1 and CXCR2) in neutrophils, resulting in the protective ability of neutrophils migration into arthritic joints. Mice were treated with thiogycollate medium intraperitoneally. After 3 days, peritoneal macrophages were isolated from three WT or TIARP-deficient mice, and these cells were stimulated by TNF? for 24 hours. Ly6G+ Neutrophils were isolated from splenocytes by MACS.
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2015-11-12 | E-GEOD-63298 | biostudies-arrayexpress
Project description:Neutrophils play critical roles in modulating the immune response. However, neutrophils have a short circulating half life, are readily stimulated in vitro, and have low levels of cellular mRNA when compared to other blood leukocyte populations. All of these factors have made it difficult to evaluate neutrophils from clinical populations for molecular and functional studies. Here we present a robust methodology for rapidly isolating neutrophils directly from whole blood and develop âon- chipâ processing for mRNA and protein isolation for genomics and proteomics. We validate this device with an ex vivo stimulation experiment and demonstrate the ability of the device to discriminate subtle differences in the genomic and proteomic response of peripheral blood neutrophils to direct and indirect stimulation. Lastly, we implement this tool as part of a near patient blood processing system within a multi-center clinical study of the immune response to severe trauma and burn injury and demonstrate that this technique is easy to use by nurses and technical staff yielding excellent quality and sufficient quantity of mRNA for sensitive genomic readout of the host response to injury 1. Ex vivo Stimulation Studies: We assessed whether the relatively small number of isolated neutrophils captured by the microfluidics cassettes would impact the resulting genomic sensitivity and potential discriminatory genomic capabilities in response to various stimuli. To do this, we compared the genome-wide expression profile in neutrophils from 4 independent repeated experiements under three conditions - untimulated, ex vivo activation with either Escherichia coli lipopolysaccharide (LPS), or with granulocyte-macrophage colony-simulating factor (GM-CSF) and interferon-gamma (INF-g) (referred to as GM+I). In both protocols, whole blood was stimulated ex vivo24 to allow leukocyte and plasma protein interactions. 2. Inter-subject Reproducibility: To further ensure the reliability of the of the microfluidics cassette isolation method, we directly compared the gene expression of neutrophils captured in the microfluidics cassettes with neutrophils isolated using density centrifugation with Ficoll-dextran. We performed parallel neutrophil isolations using both methodologies from five different healthy volunteers and processed the cell lysates for microarray analysis using identical protocols.
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Project description:Neutrophils form the most abundant leukocyte subset and are central to many disease processes. Technical challenges in transcriptomic profiling have prohibited genetical genomic approaches to date. Here, we map expression quantitative trait loci (eQTL) in peripheral blood CD16+ neutrophils from 101 healthy European adults. This dataset includes expression data from neutrophils. The genotypes and expression data from monocytes can be found in E-MTAB-2232 - Genetics of gene expression across innate immune stimulation in primary monocytes.
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