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Cyclic hypoxia induces transcriptomic changes in mast cells leading to a hyperresponsive phenotype after FcεRI crosslinking

ABSTRACT: Mast cells (MCs) play an important role in tumor development, executing pro or antitumoral functions depending on tumor type and local conditions present in the tumor microenvironment such as cyclic hypoxia (cyH), which is a distinguishing feature of almost all solid tumors. In this study, we analyzed transcriptional changes of murine bone marrow-derived mast cells (BMMCs) exposed to an in vitro protocol of cyH, consisting of interleaved cycles of hypoxia and re-oxygenation at 1% and 21% of oxygen, respectively. Utilizing a mouse M22K microarray (Microarray Unit, Cellular Physiology Institute, UNAM, Mexico City), we identified 2512 genes in MCs subjected to cyH whose expression displayed changes compared with normoxic cells. Furthermore, functional enrichment analysis revealed that cyH-related transcriptomic alterations were for genes associated with oxidative phosphorylation and the FcεRI signaling pathway. Interestingly, after IgE/ antigen (Ag) challenge, FcεRI-dependent degranulation, calcium mobilization, and PLC-γ activity were enhanced in BMMCs exposed to cyH compared to those cells maintained in normoxic conditions. In addition, the expression of calcium signaling-related cytokines such as TNF-α, IL-4, and IL-2 was increased in BMMCs exposed to cyH after IgE/Ag challenge. Taken together, these findings indicate that cyH induces transcriptomic modifications in MCs that are translated into a phenotypic change characterized by hyperresponsiveness to IgE/Ag challenge.

ORGANISM(S): Mus musculus

PROVIDER: GSE201828 | GEO | 2022/05/01

REPOSITORIES: GEO

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Expression data from activated and non-activated NTAL knockout, wild type and knockdown bone marrow derived mast cells

Project description:Non-T cell activation linker (NTAL, also called Lab or LAT2) is a transmembrane adaptor protein involved in the high affinity IgE receptor (FcεRI) signaling in mast cells. Studies with bone marrow-derived mast cells (BMMCs) from NTAL-/- mice indicated that NTAL is a negative regulator of FcεRI signaling. In contrast, depletion of NTAL by RNA interference in human or rat mast cells suggested its positive regulatory role. To determine whether compensatory developmental alterations are responsible for the observed discrepancies, we compared FcεRI-mediated signaling events in BMMCs isolated from NTAL-/- mice or BMMCs of wild type in which NTAL expression was decreased by RNA interference. We found that when compared to corresponding controls, NTAL-deficient cells, both knockouts (KOs) and knockdowns (KDs), exhibited enhanced degranulation, calcium mobilization, tyrosine phosphorylation of linker for activation of T cells (LAT) and ERK, depolymerization of filamentous actin and chemotaxis. These data indicate that NTAL in mouse BMMCs is a negative regulator of FcεRI signaling, independently of compensatory developmental alterations. To gain more insight into NTAL function, we examined gene expression profiles of resting and antigen-activated BMMCs with NTAL KO or KD and corresponding controls and identified several genes that were more than 1.8-fold differentially expressed in resting and FcεRI-activated NTAL-deficient cells, when compared to wild-type controls. We provide evidence that at least some of these genes could be involved in regulation of cholesterol-dependent events in chemotaxis towards antigen.

2014-08-26 | GSE40731 | GEO

MicroRNA profiling of mouse bone marrow-derived mast cells during mucosal differentiation and IgE-mediated activation

Project description:The aim of this study was to investigate microRNA expression pattern and its functional relevance on the commitment toward mucosal differentiation and on IgE-mediated activation of mast cells. To identify microRNA genes the expression of which change during the differentiation and activation of murine primary mast cells in vitro, the putative committed progenitors (c-kit+ cells isolated on day 6 from differentiating cultures), immature mast cells (BMMC), mucosal-type mast cells (MMC), and IgE-activated mast cells were compared by Agilent microRNA array. RNA was isolated by miRNeasy (Qiagen) from: 1) c-kit+ cells, isolated from differentiating cultures (in the presence of IL3 and SCF) derived from the bone marrow using MACS column purification, 2) immature BMMCs obtained by cultivation of bone marrow cells in the presence of IL3 and SCF for 4 weeks, 3) mucosal-type mast cells by additional differentiation of immature BMMCs for 5 days by supplementation of IL9 and TGFbeta, and 4) activated mast cells by presensitization with anti-DNP IgE followed by IgE-crosslinking by DNP-antigen challenge for 2 hours. Agilent microRNA microarray was run on these experimental groups. Four biological replicates were included in every experimental group.

2011-01-01 | E-GEOD-24321 | biostudies-arrayexpress

Stem cell factor programs the mast cell activation phenotype

Project description:Mast cells, activated by antigen via the high affinity receptor for IgE (FcεRI), release an array of pro-inflammatory mediators that contribute to allergic disorders such as asthma and anaphylaxis. The KIT ligand, stem cell factor (SCF), is critical for mast cell expansion, differentiation and survival, and, under acute conditions, enhances mast cell activation. However, extended SCF exposure in vivo conversely protects against fatal antigen-mediated anaphylaxis. In investigating this dichotomy, we identified a novel mode of regulation of the mast cell activation phenotype through SCF-mediated programming. We found that mouse bone marrow-derived mast cells chronically exposed to SCF displayed a marked attenuation of FcεRI-mediated degranulation and cytokine production. The hypo-responsive phenotype was not a consequence of altered signals regulating calcium flux or protein kinase C, but of ineffective cytoskeletal reorganization, with evidence implicating a down-regulation of expression of the Src kinase Hck. Collectively, these findings demonstrate a major role for SCF in the homeostatic control of mast cell activation with potential relevance to mast cell-driven disease and the development of novel approaches for the treatment of allergic disorders. Mouse bone marrow-derived mast cells were treated with IL3, IL3+IL33, or IL3+SCF. Six replicates each.

2012-05-01 | E-GEOD-35332 | biostudies-arrayexpress

Stem cell factor programs the mast cell activation phenotype

2012-05-02 | GSE35332 | GEO

The Inhibitory Receptor Siglec-8 Interacts with FcεRI and Globally Inhibits Intracellular Signaling in Primary Mast Cells Upon Activation

Project description:Immunomodulation of mast cell (MC) activity is warranted in allergic and inflammatory diseases where MCs have a central role in pathogenesis. Targeting Siglec-8, an inhibitory receptor on MCs and eosinophils, has shown promising activity in preclinical and clinical studies. While the intracellular pathways that regulate Siglec-8 activity in eosinophils have been well studied, the signaling mechanisms that lead to MC inhibition have not been fully elucidated. Here, we evaluate the intracellular signaling pathways of Siglec‐8‐mediated inhibition in primary MCs using an anti‐Siglec‐8 monoclonal antibody (mAb). Phospho‐proteomic profiling of FcεRI‐activated MCs revealed Siglec-8 mAb-treatment globally inhibited proximal and downstream kinases, leading to attenuated MC activation and degranulation. In fact, Siglec‐8 was found to directly interact with FcεRI signaling molecules. Siglec‐8 inhibition was dependent on both cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIMs) that interact with the SH2 containing protein phosphatase Shp-2 upon Siglec-8 phosphorylation. Taken together, these data support a model in which Siglec-8 regulates proximal FcεRI‐induced phosphorylation events through phosphatase recruitment and interaction with FcεRI, resulting in global inhibition of MCs upon Siglec-8 mAb engagement.

2022-01-21 | PXD030820 | Pride

Transcriptomic profiling of bone marrow derived mast cells (BMMCs) [RNA-seq]

Project description:Allergy is one of the least understood immunological response partly due to the diversity of allergens and the complexity of immune response against them. In allergic responses, mast cells are key players with their ability to rapidly degranulate and also generate de novo lipids and transcripts. Although the molecular details of degranulation in mast cell were studied in allergic inflammation, the transcriptional response involving chromatin remodeling, enhancer dynamics and long non-coding RNA (lncRNA) expression are largely unexplored. Here, using mouse bone marrow derived mast cells (BMMCs), we characterized the steady state, immunoglobulin E (IgE) and antigen (Ag) mediated epigenetic changes in mast cell chromatin and described the enhancer, super-enhancer and mRNA, lncRNA catalogue in these cells.

2019-12-01 | GSE75526 | GEO

Epigenetic profiling of mouse bone marrow derived mast cells (BMMCs) [ChIP-seq]

2019-12-01 | GSE75525 | GEO

Distinct 5-methylcytosine profiles in poly(A)RNA from mouse bone marrow derived mast cells

Project description:Purpose: To transcriptome widely reveal 5-mC regulation by Tet2, we performed bisulfite-sequencing of mRNAs from Tet2-deficient BMMCs and the control cells.Methods: Mouse BMMCs were generated from bone marrow cells in RPMI-1640 medium with recombinant mouse IL-3 and SCF. BMMCs were stained to confirm the surface expression of FcɛRI and c-Kit. Cells with purity >97.5% were used for RNA isolation. Results: We carried out an unbiased global analysis of m5C in poly(A)RNA of mouse bone marrow derived mast cells (BMMCs).We show that there were indeed much more mCs in Tet2-deficient group compared with the control, more than half of which located in genic region. Furthermore, we observed that although much less mCs distributed in the three elements of exon regions, more mCs located in 3`-UTR for Tet2-deficient group compared with the control.

2018-01-25 | GSE100719 | GEO

IgE antibodies increase honeybee venom responsiveness and detoxification efficiency of mast cells

Project description:In contrast to their clearly defined roles in allergic diseases, the physiologic functions of Immunoglobulin E antibodies (IgEs) and mast cells (MCs) remain enigmatic. Recent research supports the toxin hypothesis, showing that MCs and IgE-related type 2 immune responses can enhance host defense against certain noxious substances, including honeybee venom (BV). However, the mechanisms by which MCs can interfere with BV toxicity are unknown. In this study, we assessed the role of IgE and certain MC products in MC-mediated BV detoxification. We applied in vitro and in vivo fluorescence microscopy imaging, and flow cytometry, fibroblast-based toxicity assays and mass spectrometry to investigate IgE-mediated detoxification of BV cytotoxicity by mouse and human MCs in vitro. Pharmacologic strategies to interfere with MC-derived heparin and proteases helped to define the importance of specific detoxification mechanisms. Venom-specific IgE increased the degranulation and cytokine responses of MCs to BV in vitro. Passive serum sensitization enhanced MC degranulation in vivo. IgE-activated mouse or human MCs exhibited enhanced potential for detoxifying BV by both proteolytic degradation and heparin-related interference with toxicity. Mediators released by IgE-activated human MCs efficiently degraded multiple BV toxins. Our results both reveal that IgE sensitization enhances the MC’s ability to detoxify BV and also assign efficient toxin-neutralizing activity to MC-derived heparin and proteases. Our study thus highlights the potential importance of IgE, MCs, and particular MC products in defense against BV.

2021-11-25 | PXD023851 | Pride

Transcriptional heterogeneity of mast cells and basophils upon activation.

Project description:Mast cells and basophils are developmentally related cells whose activation is a hallmark of allergy. Functionally, mast cells and basophils overlap in their ability to produce several mediators, including histamine and granule proteases, but studies have increasingly demonstrated non-redundant roles. To characterize the transcriptional heterogeneity of mast cells and basophils upon their activation, we performed large-scale comparative microarrays of murine bone marrow–derived mast cells (BMMCs) and basophils (BMBs) at rest, upon an adaptive-type activation (IgE crosslinking), or upon an innate-type activation (IL-33 stimulation). Hierarchical clustering demonstrated that BMMCs and BMBs shared specific activation-associated transcriptional signatures but differed in others, both between cell type and between activation mode. In BMMCs, IgE crosslinking upregulated 785 genes including Egr2, Ccl1, and Fxyd6, while IL-33 stimulation induced 823 genes including Ccl1, Egr2, and Il1b. Focused bioinformatics pathway analysis demonstrated that IgE activation aligned with processes such as oxidative phosphorylation, angiogenesis, and the p53 pathway. The IL-33–activated transcriptome was enriched in genes commonly altered by NF-B in response to TNF, by IL-6 via STAT3, and in response to IFN. Furthermore, BMBs activated via IgE crosslinking selectively induced immune response genes Ccl1, Il3, and Il2 compared to IL-33–stimulated BMBs. Principal-component analysis revealed key cell- and activation-specific clustering. Overall, our data demonstrate that mast cells and basophils have cell- and activation-specific transcriptional responses and suggest that context-specific gene networks and pathways may shape how the immune system responds to allergens and innate cytokines.

2017-03-17 | GSE96696 | GEO

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