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Alternative activation of mast cells by CD4+ T helper cells

ABSTRACT: Effector CD4+ T lymphocytes (Teff) infiltrate sites of inflammation and orchestrate the immune response by instructing local leukocytes. Mast cells (MCs) are tissue sentinel cells strategically located near blood vessels and T cell rich areas. MC/Teff cells interactions shape Teff cell responses but in turn, Teff cell action on MC is still poorly understood. Here, we analyzed the human MC/Teff cells interplay through the application of RNAseq and functional assays and showed that activated Teff cells induced a specific transcriptomic program in MCs driving them toward an inflammatory phenotype. Teff cells affected key MC immune functions as they induced prostaglandin, inflammatory cytokines and chemokines production and fostered FceRI-dependent degranulation. Moreover, Teff cell induced in MCs the capacity to regulate T cell responses through a wide-range of dedicated soluble and membrane ligands. Cell-Cell communication inference based on transcriptomic data indicated that IFN-g, IL-21, IL-27 and IL-1b were the main driver of MC differentiation program.

ORGANISM(S): Homo sapiens

PROVIDER: GSE235240 | GEO | 2024/07/03

REPOSITORIES: GEO

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IL-33 induces a hypo-responsive human mast cell phenotype

Project description:Interleukin-33 (IL-33) is elevated in afflicted tissues of patients with mast cell-dependent chronic allergic diseases. Based on its acute effects on mouse mast cells (MCs), IL-33 is thought to play a role in the pathogenesis of allergic disease through MC activation. However, the manifestations of chronic IL-33 exposure on human MC function, which best reflect the conditions associated with chronic allergic disease, are unknown. We now find that long-term exposure of human and mouse MCs to IL-33 results in a substantial reduction of MC activation in response to antigen. This reduction required >72 h exposure to IL-33 for onset and 1-2 wk for reversion following IL-33 removal. This hypo-responsive phenotype was determined to be a consequence of MyD88-dependent attenuation of signaling processes necessary for MC activation including antigen-mediated calcium mobilization and cytoskeletal reorganization; potentially as a consequence of down-regulation of the expression of PLCg1 and Hck. These findings suggest that IL-33 may play a protective, rather than a causative role in MC activation under chronic conditions and, furthermore, reveal regulated plasticity in the MC activation phenotype. The ability to down-regulate MC activation in this manner may provide alternative approaches for treatment of MC-driven disease. Mouse bone marrow-derived mast cells treated with IL3 or IL3+IL33. 6 replicates each.

2013-02-06 | E-GEOD-39382 | biostudies-arrayexpress

IL-33 induces a hypo-responsive human mast cell phenotype

2013-02-06 | GSE39382 | GEO

Gene expression data of human peripheral blood-derived cultured mast cells

Project description:Mast cell (MC) activation contributes considerably to immune responses, such as host protection and allergy. Cell surface immunoreceptors expressed on MCs play an important role in MC activation. Although various immunoreceptors on MCs have been identified, the regulatory mechanism of MC activation is not fully understood. To understand the regulatory mechanisms of MC activation, we used gene expression analyses of human MCs to identify a novel immunoreceptor expressed on MCs. We found that Tek, which encodes Tie2, was preferentially expressed in the MCs of humans.

2015-12-21 | GSE71247 | GEO

Mast cell intracellular traps (MIT) release neutrophil effector proteins during degranulation and nexocytosis

Project description:Degranulating mast cells (MCs) release inflammatory mediators (proteins, lipids, small molecules), including chemokines and chemoattractants, which recruit other immune cells in tissues. Neutrophils can initiate self-amplifying swarming responses via intercellular communication through the lipid leukotriene B4 (LTB4). Initially discovered by two-photon intravital microscopy in mice and confocal live cell imaging, we show that degranulating MCs release LTB4 and exploit this attractant by re-directing neutrophils to MCs. In a process generally termed entosis, neutrophil cluster formation around MCs results in the trapping of living neutrophils inside MC vacuoles in vivo and in vitro. Thus, we identify a novel cell-in-cell structure between MCs and neutrophils, which we term “Mast Cell Intracellular Trap” (MIT). Compared to MCs, MITs revealed improved MC metabolism and recovery after degranulation. This leads to several benefits for MITs: (1) they can be more efficiently re-stimulated than MCs, (2) they show improved survival under nutrient limitation, and (3) MITs store neutrophil proteins, DNA and effector molecules, which can be released after re-stimulation. In this context, we compare the secretome (secreted proteins) of MCs and MITs (in cell culture) before and subsequent to degranulation via label-free nanoLC-MS. In summary, mast cells trap and cannibalize swarming neutrophils, which supply nutrients, proteins and inflammatory molecules to recovering MCs. Our studies may have potential implications for chronically activated MCs in MC-related immune disorders.

2024-06-18 | PXD044140 | Pride

Characterization of the novel spontaneously immortalized rat Müller cell line SIRMu-1

Project description:Müller cells (MCs) play a crucial role in the retina, and cultured MC lines are an important tool with which to study MC function. Transformed MC lines have been widely used; however, the transformation process can also lead to unwanted changes compared to the primary cells from which they were derived. A monoclonal spontaneously immortalized rat Müller cell line, SIRMu-1, was derived from primary rat MCs and characterized by RNA-sequencing (in addition to immunofluorescence and western blotting) in comparison to primary MCs and the SV40-immortalized MC line, rMC-1.

2018-12-01 | GSE123161 | 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

IL-33 induces an antiviral signature in mast cells but enhances their permissiveness for human rhinovirus infection

Project description:Mast cells (MCs) are classically associated with allergic asthma but their role in antiviral immunity is unclear. Human rhinoviruses (HRVs) are a major cause of asthma exacerbations and can infect and replicate within MCs. The primary site of HRV infection is the airway epithelium and MCs localise to this site with increasing asthma severity. The asthma susceptibility gene, IL-33, encodes an epithelial-derived cytokine released following HRV infection but its impact on MC antiviral responses has yet to be determined. In this study we investigated the global response of LAD2 MCs to IL-33 stimulation using RNA sequencing and identified genes involved in antiviral immunity. In spite of this, IL-33 treatment increased permissiveness of MCs to HRV16 infection which, from the RNA-Seq data, we attributed to upregulation of ICAM1. Flow cytometric analysis confirmed an IL-33-dependent increase in ICAM1 surface expression as well as LDLR, the receptors used by major and minor group HRVs for cellular entry. Neutralisation of ICAM1 reduced the IL-33-dependent enhancement in HRV16 replication and release in both LAD2 MCs and cord blood derived MCs. These findings demonstrate that although IL-33 induces an antiviral signature in MCs, it also upregulates the receptors for HRV entry to enhance infection. This highlights the potential for a gene-environment interaction involving IL33 and HRV in MCs to contribute to virus-induced asthma exacerbations.

2022-11-01 | GSE216269 | GEO

Mast cell-derived SAMD14 is a novel regulator of the human prostate tumor microenvironment

Project description:Mast cells (MCs) are important cellular components of the tumor microenvironment and are significantly associated with poor patient outcomes in prostate cancer and other solid cancers. The promotion of tumor progression partly involves heterotypic interactions between MCs and cancer-associated fibroblasts (CAFs) which combine to potentiate a pro-tumor extracellular matrix and promote epithelial cell invasion and migration. Thus far, the interactions between MCs and CAFs remains poorly understood. To identify molecular changes that may alter resident MC function in the prostate tumor microenvironment, we profiled the transcriptome of human prostate MCs, isolated from patient-matched non-tumor and tumor-associated regions of fresh radical prostatectomy tissue. Transcriptomic profiling revealed a distinct gene expression profile of MCs isolated from prostate tumor regions, including the downregulation of SAMD14, a putative tumor suppressor gene. Proteomic profiling revealed overexpression of SAMD14 in HMC-1 MCs altered the secretion of proteins associated with immune regulation and extracellular matrix processes. To assess MC biological function within a model of the prostate tumor microenvironment, HMC-1-SAMD14+ conditioned media was added to co-cultures of primary prostatic CAFs and prostate epithelium. HMC-1-SAMD14+ secretions were shown to reduce the deposition and alignment of matrix produced by CAFs and suppress pro-tumorigenic prostate epithelial morphology. Overall, our data presents the first profile of human MCs derived from patient prostate cancer specimens and identifies MC-derived SAMD14 as an important mediator of MC phenotype and function within the prostate tumor microenvironment.

2021-03-12 | PXD022782 | Pride

A novel approach for studying mast cell-driven disorders: mast cells derived from induced pluripotent stem cells

Project description:We developed a novel strategy for the rapid and efficient differentiation of MCs from human induced pluripotent stem cells (hiPSC). These hiPSC-derived MCs (hiPSC-MCs) exhibit phenotypic and functional characteristics of human skin MCs (hsMCs) and peripheral hematopoietic stem cell-derived MCs (PSCMCs). hiPSC-MCs display stable expression of MC-associated receptors such as CD117, FcεRIα and MRGPRX2, and degranulate by stimulation with IgE/anti-IgE and Substance. P.

2022-08-31 | GSE181457 | GEO

Mast Cells Control Lung Type 2 Inflammation via Prostaglandin E2-Driven Soluble ST2.

Project description:Severe asthma and sinus disease is a consequence of Type 2 inflammation (T2I), mediated by IL-33 signaling through its membrane-bound receptor, ST2. Soluble (s)ST2 reduces available IL-33 and limits T2I, but little is known about its regulation. We demonstrate that prostaglandin E2 (PGE2) drives production of sST2 to limit features of lung T2I. PGE2 deficient mice display diminished sST2. In humans with severe respiratory T2I, urinary PGE2 metabolites correlate with serum sST2. In mice, PGE2 enhanced sST2 secretion by mast cells (MCs). Mice lacking MCs, ST2 expression by MCs or EP2 receptors by MCs showed reduced sST2 lung concentrations and strong T2I. Recombinant sST2 reduced T2I in mice lacking PGE2 or ST2 expression by MCs back to control levels. PGE2 deficiency also reversed the hyperinflammatory phenotype in mice lacking ST2 expression by MCs. PGE2 thus suppresses T2I through MC-derived sST2, explaining the severe T2I observed in low PGE2 states.

2024-05-20 | GSE266501 | GEO

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