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The Molecular Mechanisms behind Mast Cell Allergic and Innate Immune...
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The Molecular Mechanisms behind Mast Cell Allergic and Innate Immune Responses

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Immunology".

Deadline for manuscript submissions: closed (31 August 2023) | Viewed by 12257

Special Issue Editor

Prof. Dr. Ronit Sagi-Eisenberg

E-Mail Website
Guest Editor
Department of Cell and Developmental Biology, Tel Aviv University, Tel Aviv P.O. Box 39040, Israel
Interests: mast cells; exocytosis; secretory granules; Rab GTPases; lysosome related organelles

Special Issue Information

Dear Colleagues, 

Exocytosis is the final step in the secretory pathway. In professional secretory cells, including neurons, endocrine, exocrine and cells of the immune system, the secretory pathway to release proteins and other materials destined for export from cells, in a regulated fashion, following receipt of a signal applied at the cell surface. As such, exocytosis serves a central role in cell communication with its environment and the coordination of its cellular functions. In immune cells, such as mast cells, regulated exocytosis mediates their immediate response, which leads to the release of a variety of inflammatory mediators that are pre-formed and stored in cytoplasmic secretory granules (SGs). Therefore, mast cell exocytosis plays a central role in mediating mast cell pathological responses in allergy and anaphylaxis, and their physiological innate immune responses, in their capacity as sentinel cells of the immune system. Yet, the mechanisms that underlie mast cell degranulation are still not entirely understood. Questions that await further investigation concern the mechanism behind the biogenesis of the mast cell SGs; do they share mechanisms with other lysosome-related organelles, or rather, with other secretory cells? Their precise mechanisms of coupling signaling with secretion and the precise role of the cytoskeleton, actin and microtubules in controlling exocytosis are yet to be investigated. Given the heterogeneity of mast cells, the heterogeneity of their SGs, the multiple stimuli mast cells respond to and the fact that mast cells can utilize distinct modes of exocytosis to release their SG content, it is envisioned that the mechanisms that control mast degranulation and the release of their SG content are complex and not necessarily unifying. This Special Issue aims to create a collection of original research and review articles that address different aspects of mast cell secretion.

Prof. Dr. Ronit Sagi-Eisenberg
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • degranulation
  • exocytosis
  • secretory granules
  • stimulus–secretion coupling
  • actin
  • microtubules
  • cytoskeleton

Published Papers (5 papers)

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Research

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31 pages, 6016 KiB  
Article
Enhanced Membrane Fluidization and Cholesterol Displacement by 1-Heptanol Inhibit Mast Cell Effector Functions
by Viktor Bugajev, Lubica Draberova, Pavol Utekal, Michaela Blazikova, Magda Tumova and Petr Draber
Cells 2023, 12(16), 2069; https://doi.org/10.3390/cells12162069 - 15 Aug 2023
Viewed by 1327
Abstract
Signal transduction by the high-affinity IgE receptor (FcεRI) depends on membrane lipid and protein compartmentalization. Recently published data show that cells treated with 1-heptanol, a cell membrane fluidizer, exhibit changes in membrane properties. However, the functional consequences of 1-heptanol-induced changes on mast cell [...] Read more.
Signal transduction by the high-affinity IgE receptor (FcεRI) depends on membrane lipid and protein compartmentalization. Recently published data show that cells treated with 1-heptanol, a cell membrane fluidizer, exhibit changes in membrane properties. However, the functional consequences of 1-heptanol-induced changes on mast cell signaling are unknown. This study shows that short-term exposure to 1-heptanol reduces membrane thermal stability and dysregulates mast cell signaling at multiple levels. Cells treated with 1-heptanol exhibited increased lateral mobility and decreased internalization of the FcεRI. However, this did not affect the initial phosphorylation of the FcεRI-β chain and components of the SYK/LAT1/PLCγ1 signaling pathway after antigen activation. In contrast, 1-heptanol inhibited SAPK/JNK phosphorylation and effector functions such as calcium response, degranulation, and cytokine production. Membrane hyperfluidization induced a heat shock-like response via increased expression of the heat shock protein 70, increased lateral diffusion of ORAI1-mCherry, and unsatisfactory performance of STIM1-ORAI1 coupling, as determined by flow-FRET. Furthermore, 1-heptanol inhibited the antigen-induced production of reactive oxygen species and potentiated stress-induced plasma membrane permeability by interfering with heat shock protein 70 activity. The combined data suggest that 1-heptanol-mediated membrane fluidization does not interfere with the earliest biochemical steps of FcεRI signaling, such as phosphorylation of the FcεRI-β chain and components of the SYK/LAT/PLCγ1 signaling pathway, instead inhibiting the FcεRI internalization and mast cell effector functions, including degranulation and cytokine production. Full article
(This article belongs to the Special Issue The Molecular Mechanisms behind Mast Cell Allergic and Innate Immune Responses)
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17 pages, 3899 KiB  
Article
Mast Cell Interaction with Foxp3+ Regulatory T Cells Occur in the Dermis after Initiation of IgE-Mediated Cutaneous Anaphylaxis
by Rasha Msallam, Bernard Malissen, Pierre Launay, Ulrich Blank, Gregory Gautier and Jean Davoust
Cells 2022, 11(19), 3055; https://doi.org/10.3390/cells11193055 - 29 Sep 2022
Cited by 2 | Viewed by 1752
Abstract
Mast cells (MCs) are well-known for their role in IgE-mediated cutaneous anaphylactic responses, but their regulatory functions in the skin are still under intense scrutiny. Using a Red MC and Basophil reporter (RMB) mouse allowing red fluorescent detection and diphtheria toxin mediated depletion [...] Read more.
Mast cells (MCs) are well-known for their role in IgE-mediated cutaneous anaphylactic responses, but their regulatory functions in the skin are still under intense scrutiny. Using a Red MC and Basophil reporter (RMB) mouse allowing red fluorescent detection and diphtheria toxin mediated depletion of MCs, we investigated the interaction of MCs, Foxp3+ regulatory T lymphocytes (Tregs) and Langerhans cells (LCs) during passive cutaneous anaphylaxis (PCA) responses. Using intravital imaging we show that MCs are sessile at homeostasis and during PCA. Breeding RMB mice with Langerin-eGFP mice revealed that dermal MCs do not interact with epidermal-localized LCs, the latter showing constant sprouting of their dendrites at homeostasis and during PCA. When bred with Foxp3-eGFP mice, we found that, although a few Foxp3+ Tregs are present at homeostasis, many Tregs transiently infiltrated the skin during PCA. While their velocity during PCA was not altered, Tregs increased the duration of their contact time with MCs compared to PCA-control mice. Antibody-mediated depletion of Tregs had no effect on the intensity of PCA. Hence, the observed increase in Treg numbers and contact time with MCs, regardless of an effect on the intensity of PCA responses, suggests an anti-inflammatory role dedicated to prevent further MC activation. Full article
(This article belongs to the Special Issue The Molecular Mechanisms behind Mast Cell Allergic and Innate Immune Responses)
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25 pages, 3287 KiB  
Article
Cyclic Hypoxia Induces Transcriptomic Changes in Mast Cells Leading to a Hyperresponsive Phenotype after FcεRI Cross-Linking
by Deisy Segura-Villalobos, Monica Lamas and Claudia González-Espinosa
Cells 2022, 11(14), 2239; https://doi.org/10.3390/cells11142239 - 19 Jul 2022
Cited by 2 | Viewed by 2213
Abstract
Mast cells (MCs) play important roles in tumor development, executing pro- or antitumoral functions depending on tumor type and tumor microenvironment (TME) conditions. Cyclic hypoxia (cyH) is a common feature of TME since tumor blood vessels fail to provide a continuous supply of [...] Read more.
Mast cells (MCs) play important roles in tumor development, executing pro- or antitumoral functions depending on tumor type and tumor microenvironment (TME) conditions. Cyclic hypoxia (cyH) is a common feature of TME since tumor blood vessels fail to provide a continuous supply of oxygen to the tumor mass. Here, we hypothesized that the localization of MCs in cyH regions within solid tumors could modify their transcriptional profile and activation parameters. Using confocal microscopy, we found an important number of MCs in cyH zones of murine melanoma B16-F1 tumors. Applying microarray analysis to examine the transcriptome of murine bone-marrow-derived MCs (BMMCs) exposed to interleaved cycles of hypoxia and re-oxygenation, we identified altered expression of 2512 genes. Functional enrichment analysis revealed that the transcriptional signature of MCs exposed to cyH is associated with oxidative phosphorylation and the FcεRI signaling pathway. Interestingly, FcεRI-dependent degranulation, calcium mobilization, and PLC-γ activity, as well as Tnf-α, Il-4, and Il-2 gene expression after IgE/antigen challenge were increased in BMMCs exposed to cyH compared with those maintained in normoxia. Taken together, our findings indicate that cyH causes an important phenotypic change in MCs that should be considered in the design of inflammation-targeted therapies to control tumor growth. Full article
(This article belongs to the Special Issue The Molecular Mechanisms behind Mast Cell Allergic and Innate Immune Responses)
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Review

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14 pages, 1116 KiB  
Review
The Controversial Role of Intestinal Mast Cells in Colon Cancer
by Rosa Molfetta and Rossella Paolini
Cells 2023, 12(3), 459; https://doi.org/10.3390/cells12030459 - 31 Jan 2023
Cited by 5 | Viewed by 2649
Abstract
Mast cells are tissue-resident sentinels involved in large number of physiological and pathological processes, such as infection and allergic response, thanks to the expression of a wide array of receptors. Mast cells are also frequently observed in a tumor microenvironment, suggesting their contribution [...] Read more.
Mast cells are tissue-resident sentinels involved in large number of physiological and pathological processes, such as infection and allergic response, thanks to the expression of a wide array of receptors. Mast cells are also frequently observed in a tumor microenvironment, suggesting their contribution in the transition from chronic inflammation to cancer. In particular, the link between inflammation and colorectal cancer development is becoming increasingly clear. It has long been recognized that patients with inflammatory bowel disease have an increased risk of developing colon cancer. Evidence from experimental animals also implicates the innate immune system in the development of sporadically occurring intestinal adenomas, the precursors to colorectal cancer. However, the exact role of mast cells in tumor initiation and growth remains controversial: mast cell-derived mediators can either exert pro-tumorigenic functions, causing the progression and spread of the tumor, or anti-tumorigenic functions, limiting the tumor’s growth. Here, we review the multifaceted and often contrasting findings regarding the role of the intestinal mast cells in colon cancer progression focusing on the molecular pathways mainly involved in the regulation of mast cell plasticity/functions during tumor progression. Full article
(This article belongs to the Special Issue The Molecular Mechanisms behind Mast Cell Allergic and Innate Immune Responses)
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30 pages, 833 KiB  
Review
Targeting Mast Cells in Allergic Disease: Current Therapies and Drug Repurposing
by Jason R. Burchett, Jordan M. Dailey, Sydney A. Kee, Destiny T. Pryor, Aditya Kotha, Roma A. Kankaria, David B. Straus and John J. Ryan
Cells 2022, 11(19), 3031; https://doi.org/10.3390/cells11193031 - 27 Sep 2022
Cited by 9 | Viewed by 3653
Abstract
The incidence of allergic disease has grown tremendously in the past three generations. While current treatments are effective for some, there is considerable unmet need. Mast cells are critical effectors of allergic inflammation. Their secreted mediators and the receptors for these mediators have [...] Read more.
The incidence of allergic disease has grown tremendously in the past three generations. While current treatments are effective for some, there is considerable unmet need. Mast cells are critical effectors of allergic inflammation. Their secreted mediators and the receptors for these mediators have long been the target of allergy therapy. Recent drugs have moved a step earlier in mast cell activation, blocking IgE, IL-4, and IL-13 interactions with their receptors. In this review, we summarize the latest therapies targeting mast cells as well as new drugs in clinical trials. In addition, we offer support for repurposing FDA-approved drugs to target mast cells in new ways. With a multitude of highly selective drugs available for cancer, autoimmunity, and metabolic disorders, drug repurposing offers optimism for the future of allergy therapy. Full article
(This article belongs to the Special Issue The Molecular Mechanisms behind Mast Cell Allergic and Innate Immune Responses)
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