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Mast Cells in Inflammation and Immunity

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

Deadline for manuscript submissions: closed (15 March 2019) | Viewed by 54250

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Dr. Adrian M. Piliponsky

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Guest Editor

1 Department of Pediatrics, University of Washington, Seattle, WA, USA
2 Department of Pathology, University of Washington, Seattle, WA, USA
3 Center for Immunity and Immunotherapies, Seatlle Children’s Research Institute, Seattle, WA, USA
Interests: mast cells; inflammation; bacterial infection; sepsis

Special Issue Information

Dear Colleagues,

Mast cells are long-living, granule-containing immune cells that are widely distributed in tissues that interact with the external environment, such as the skin and mucosal tissues. The roles of mast cells in IgE-mediated allergic reactions are well-established; however, because of their location, it has also long been hypothesized that mast cells can promote innate immunity against pathogens.

In this Special Issue of Cells, we invite your contribution, either in the form of original research articles, reviews, or shorter perspective articles on all aspects related to the theme of “Mast Cells in Inflammation and Immunity”. Articles with mechanistic and functional insights from a cell, molecular biology, or in vivo studies perspective are specially welcome. Relevant topics include, but are not limited to:

Pathogen recognition and mast cell activation in the innate immune response
Contribution of mast cell mediators to innate immunity
Differential release of mast cell mediators in innate immunity
In vivo models to investigate mast cell-dependent responses in innate immunity
Mast cell microbicidal activity
Microbiome-mast cell interaction effects on the innate immune response against pathogens
Regulation of mast cell function during innate immune responses to pathogens
Contribution of mast cells to human innate immunity
“Multi-Omics” analysis of mast cell contribution to innate immunity

Dr. Adrian M. Piliponsky
Guest Editor

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Keywords

Pathogen recognition
In vivo models
Microbicidal activity
Microbiome
Immune-regulation
Human innate immunity
Multi omics
Mast cell mediators

Published Papers (10 papers)

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Research

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19 pages, 2718 KiB

Open AccessArticle

The Chymase Mouse Mast Cell Protease-4 Regulates Intestinal Cytokine Expression in Mature Adult Mice Infected with Giardia intestinalis

by Zhiqiang Li, Dimitra Peirasmaki, Staffan Svärd and Magnus Åbrink

Cells 2020, 9(4), 925; https://doi.org/10.3390/cells9040925 - 09 Apr 2020

Cited by 9 | Viewed by 3268

Abstract

Mast cells have been shown to affect the control of infections with the protozoan parasite Giardia intestinalis. Recently, we demonstrated that Giardia excretory-secretory proteins inhibited the activity of the connective tissue mast cell-specific protease chymase. To study the potential role of the chymase mouse mast cell protease (mMCP)-4 during infections with Giardia, mMCP-4^+/+ and mMCP-4^−/− littermate mice were gavage-infected with G. intestinalis trophozoites of the human assemblage B isolate GS. No significant changes in weight gain was observed in infected young (≈10 weeks old) mMCP-4^−/− and mMCP-4^+/+ littermate mice. In contrast, infections of mature adult mice (>18 weeks old) caused significant weight loss as compared to uninfected control mice. We detected a more rapid weight loss in mMCP-4^−/− mice as compared to littermate mMCP-4^+/+ mice. Submucosal mast cell and granulocyte counts in jejunum increased in the infected adult mMCP-4^−/− and mMCP-4^+/+ mice. This increase was correlated with an augmented intestinal trypsin-like and chymotrypsin-like activity, but the myeloperoxidase activity was constant. Infected mice showed a significantly lower intestinal neutrophil elastase (NE) activity, and in vitro, soluble Giardia proteins inhibited human recombinant NE. Serum levels of IL-6 were significantly increased eight and 13 days post infection (dpi), while intestinal IL-6 levels showed a trend to significant increase 8 dpi. Strikingly, the lack of mMCP-4 resulted in significantly less intestinal transcriptional upregulation of IL-6, TNF-α, IL-25, CXCL2, IL-2, IL-4, IL-5, and IL-10 in the Giardia-infected mature adult mice, suggesting that chymase may play a regulatory role in intestinal cytokine responses. Full article

(This article belongs to the Special Issue Mast Cells in Inflammation and Immunity)

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15 pages, 3867 KiB

Open AccessArticle

Possible Involvement of Intracellular Calcium-Independent Phospholipase A₂ in the Release of Secretory Phospholipases from Mast Cells—Increased Expression in Ileal Mast Cells of Crohn’s Disease

by Ulrika Christerson, Åsa V. Keita, Martin E. Winberg, Johan D. Söderholm and Christina Gustafson-Svärd

Cells 2019, 8(7), 672; https://doi.org/10.3390/cells8070672 - 03 Jul 2019

Cited by 3 | Viewed by 3635

Abstract

Increased activity of secretory phospholipases A₂ (sPLA₂) type-II was previously observed in ileum of Crohn’s disease (CD). Our aims were to explore the involvement of calcium-independent (i)PLA₂β in the release of sPLA₂s from the human mast cell (MC) line (HMC-1) and investigate expressions of cytosolic (c)PLA₂α, iPLA₂β, sPLA₂-IIA and sPLA₂-V in MCs of CD ileum. The release of sPLA₂ was investigated in HMC-1 by immunocytochemistry and ELISA. The expression intensities of PLA₂s in mucosal MCs, and the proportion of PLA₂-positive MCs, were investigated in normal ileum and in ileum from patients with CD by immunohistochemistry. The calcium ionophore-stimulated release of sPLA₂-IIA and sPLA₂-V from HMC-1 was reduced by the iPLA₂-inhibitor bromoenol lactone. All four PLA₂s were detectable in mucosal MCs, both in normal ileum and in CD, but the proportion of iPLA₂β-containing mucosal MCs and the expression intensity of sPLA₂-IIA was increased in CD. Results indicate that iPLA₂β is involved in the secretion of sPLA₂s from HMC-1, and suggest that iPLA₂β-mediated release of sPLA₂ from intestinal MCs may contribute to CD pathophysiology. Ex vivo studies on isolated mucosal mast cells are however needed to clarify the precise role of MC PLA₂s in the inflammatory processes of CD. Full article

(This article belongs to the Special Issue Mast Cells in Inflammation and Immunity)

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16 pages, 2963 KiB

Open AccessArticle

Mast Cell Protease 7 Promotes Angiogenesis by Degradation of Integrin Subunits

by Devandir A. de Souza Junior, Carolina Santana, Gabriel V. Vieira, Constance Oliver and Maria Celia Jamur

Cells 2019, 8(4), 349; https://doi.org/10.3390/cells8040349 - 12 Apr 2019

Cited by 1 | Viewed by 3063

Abstract

Previous studies from our laboratory have shown that during angiogenesis in vitro, rmMCP-7 (recombinant mouse mast cell protease-7) stimulates endothelial cell spreading and induces their penetration into the matrix. The ability of rmMCP-7 to induce angiogenesis in vivo was assessed in the present study using a directed in vivo angiogenesis assay (DIVAA™). Vessel invasion of the angioreactor was observed in the presence of rmMCP-7 but was not seen in the control. Since integrins are involved in endothelial cell migration, the relationship between rmMCP-7 and integrins during angiogenesis was investigated. Incubation with rmMCP-7 resulted in a reduction in the levels of integrin subunits αv and β1 on SVEC4-10 endothelial cells during angiogenesis in vitro. Furthermore, the degradation of integrin subunits occurs both through the direct action of rmMCP-7 and indirectly via the ubiquitin/proteasome system. Even in the presence of a proteasome inhibitor, incubation of endothelial cells with rmMCP-7 induced cell migration and tube formation as well as the beginning of loop formation. These data indicate that the direct degradation of the integrin subunits by rmMCP-7 is sufficient to initiate angiogenesis. The results demonstrate, for the first time, that mMCP-7 acts in angiogenesis through integrin degradation. Full article

(This article belongs to the Special Issue Mast Cells in Inflammation and Immunity)

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17 pages, 1811 KiB

Open AccessArticle

IL-33 and MRGPRX2-Triggered Activation of Human Skin Mast Cells—Elimination of Receptor Expression on Chronic Exposure, but Reinforced Degranulation on Acute Priming

by Zhao Wang, Sven Guhl, Kristin Franke, Metin Artuc, Torsten Zuberbier and Magda Babina

Cells 2019, 8(4), 341; https://doi.org/10.3390/cells8040341 - 11 Apr 2019

Cited by 40 | Viewed by 5503

Abstract

Clinically relevant exocytosis of mast cell (MC) mediators can be triggered by high-affinity IgE receptor (FcεRI)-aggregation (allergic route) or by the so-called pseudo-allergic pathway elicited via MAS-related G protein-coupled receptor-X2 (MRGPRX2). The latter is activated by drugs and endogenous neuropeptides. We recently reported that FcεRI-triggered degranulation is attenuated when human skin mast cells are chronically exposed to IL-33. Here, we were interested in the regulation of the MRGPRX2-route. Chronic exposure of skin MCs to IL-33 basically eliminated the pseudo-allergic/neurogenic route as a result of massive MRGPRX2 reduction. This downregulation seemed to partially require c-Jun N-terminal Kinase (JNK), but not p38, the two kinases activated by IL-33 in skin MCs. Surprisingly, however, JNK had a positive effect on MRGPRX2 expression in the absence of IL-33. This was evidenced by Accell^®-mediated JNK knockdown and JNK inhibition. In stark contrast to the dampening effect upon prolonged exposure, IL-33 was able to prime for increased degranulation by MRGPRX2 ligands when administered directly before stimulation. This supportive effect depended on p38, but not on JNK activity. Our data reinforce the concept that exposure length dictates whether IL-33 will enhance or attenuate secretion. IL-33 is, thus, the first factor to acutely enhance MRGPRX2-triggered degranulation. Finally, we reveal that p38, rarely associated with MC degranulation, can positively affect exocytosis in a context-dependent manner. Full article

(This article belongs to the Special Issue Mast Cells in Inflammation and Immunity)

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12 pages, 2347 KiB

Open AccessArticle

Flow Cytometry-Based Characterization of Mast Cells in Human Atherosclerosis

by Eva Kritikou, Marie A.C. Depuydt, Margreet R. de Vries, Kevin E. Mulder, Arthur M. Govaert, Marrit D. Smit, Janine van Duijn, Amanda C. Foks, Anouk Wezel, Harm J. Smeets, Bram Slütter, Paul H.A. Quax, Johan Kuiper and Ilze Bot

Cells 2019, 8(4), 334; https://doi.org/10.3390/cells8040334 - 09 Apr 2019

Cited by 27 | Viewed by 6957

Abstract

The presence of mast cells in human atherosclerotic plaques has been associated with adverse cardiovascular events. Mast cell activation, through the classical antigen sensitized-IgE binding to their characteristic Fcε-receptor, causes the release of their cytoplasmic granules. These granules are filled with neutral proteases such as tryptase, but also with histamine and pro-inflammatory mediators. Mast cells accumulate in high numbers within human atherosclerotic tissue, particularly in the shoulder region of the plaque. These findings are largely based on immunohistochemistry, which does not allow for the extensive characterization of these mast cells and of the local mast cell activation mechanisms. In this study, we thus aimed to develop a new flow-cytometry based methodology in order to analyze mast cells in human atherosclerosis. We enzymatically digested 22 human plaque samples, collected after femoral and carotid endarterectomy surgery, after which we prepared a single cell suspension for flow cytometry. We were able to identify a specific mast cell population expressing both CD117 and the FcεR, and observed that most of the intraplaque mast cells were activated based on their CD63 protein expression. Furthermore, most of the activated mast cells had IgE fragments bound on their surface, while another fraction showed IgE-independent activation. In conclusion, we are able to distinguish a clear mast cell population in human atherosclerotic plaques, and this study establishes a strong relationship between the presence of IgE and the activation of mast cells in advanced atherosclerosis. Our data pave the way for potential therapeutic intervention through targeting IgE-mediated actions in human atherosclerosis. Full article

(This article belongs to the Special Issue Mast Cells in Inflammation and Immunity)

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17 pages, 2041 KiB

Open AccessArticle

Small-Molecule Host-Defense Peptide Mimetic Antibacterial and Antifungal Agents Activate Human and Mouse Mast Cells via Mas-Related GPCRs

by Ibrahim Alkanfari, Katie B. Freeman, Saptarshi Roy, Tahsin Jahan, Richard W. Scott and Hydar Ali

Cells 2019, 8(4), 311; https://doi.org/10.3390/cells8040311 - 03 Apr 2019

Cited by 19 | Viewed by 4534

Abstract

Host-defense peptides (HDPs) have an important therapeutic potential against microbial infections but their metabolic instability and cellular cytotoxicity have limited their utility. To overcome these limitations, we utilized five small-molecule, nonpeptide HDP mimetics (smHDPMs) and tested their effects on cytotoxicity, antimicrobial activity, and mast cell (MC) degranulation. None of the smHDPMs displayed cytotoxicity against mouse 3T3 fibroblasts or human transformed liver HepG2 cells. However, one compound had both antifungal and antibacterial activity. Surprisingly, all five compounds induced degranulation in a human MC line, LAD2, and this response was substantially reduced in Mas-related G protein-coupled receptor (GPCR)-X2 (MRGPRX2)-silenced cells. Furthermore, all five compounds induced degranulation in RBL-2H3 cells expressing MRGPRX2 but this response was abolished in cells expressing naturally occurring loss-of-function missense variants G165E (rs141744602) and D184H (rs372988289). Mrgprb2 is the likely mouse ortholog of human MRGPRX2, which is expressed in connective tissue MCs (CTMCs) such as cutaneous and peritoneal MCs (PMCs). All five smHDPMs induced degranulation in wild-type PMCs but not in cells derived from Mrgprb2⁻/⁻ mice. These findings suggest that smHDPMs could serve as novel targets for the treatment of drug-resistant fungal and bacterial infections because of their ability to harness CTMCs’ host defense functions. Full article

(This article belongs to the Special Issue Mast Cells in Inflammation and Immunity)

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16 pages, 3036 KiB

Open AccessArticle

Suppression of IgE-Independent Degranulation of Murine Connective Tissue-Type Mast Cells by Dexamethasone

by Keiko Yamada, Hitomi Sato, Kazuma Sakamaki, Mayumi Kamada, Yasushi Okuno, Nobuyuki Fukuishi, Kazuyuki Furuta and Satoshi Tanaka

Cells 2019, 8(2), 112; https://doi.org/10.3390/cells8020112 - 01 Feb 2019

Cited by 12 | Viewed by 4834

Abstract

Steroidal anti-inflammatory drugs are widely used for the treatment of chronic cutaneous inflammation, such as atopic dermatitis, although it remains unknown how they modulate cutaneous mast cell functions. We investigated the effects of prolonged treatment with a synthetic glucocorticoid, dexamethasone, on murine connective tissue-type mast cells using in vitro and in vivo models. Our connective tissue-type bone marrow-derived cultured mast cell model was found to be sensitive to mast cell secretagogues, such as compound 48/80 and substance P, and higher expression levels of α subunit of a trimeric G protein, G_i1, and several Mas-related G protein-coupled receptor (Mrgpr) subtypes were observed in comparison with immature cultured mast cells. Secretagogue-induced degranulation and up-regulation of these genes was suppressed when cultured in the presence of dexamethasone. The profiles of granule constituents were drastically altered by dexamethasone. Topical application of dexamethasone down-modulated secretagogue-induced degranulation and the expression levels of several Mrgpr subtypes in cutaneous tissue. These results suggest that mast cell-mediated IgE-independent cutaneous inflammation could be suppressed by steroidal anti-inflammatory drugs through the down-regulation of G _αi1 and several Mrgpr subtypes in mast cells. Full article

(This article belongs to the Special Issue Mast Cells in Inflammation and Immunity)

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10 pages, 5700 KiB

Open AccessArticle

Lack of Endogenous Annexin A1 Increases Mast Cell Activation and Exacerbates Experimental Atopic Dermatitis

by Jéssica dos Santos Parisi, Mab Pereira Corrêa and Cristiane Damas Gil

Cells 2019, 8(1), 51; https://doi.org/10.3390/cells8010051 - 15 Jan 2019

Cited by 23 | Viewed by 4640

Abstract

Annexin A1 (AnxA1) is a protein with potent anti-inflammatory actions and an interesting target that has been poorly explored in skin inflammation. This work evaluated the lack of endogenous AnxA1 in the progression of ovalbumin (OVA)-induced atopic dermatitis (AD)-like skin lesions. OVA/Alum-immunized C57BL/6 male wild-type (WT) and AnxA1 null (AnxA1^-/-) mice were challenged with drops containing OVA on days 11, 14–18 and 21–24. The AnxA1^-/- AD group exhibited skin with intense erythema, erosion and dryness associated with increased skin thickness compared to the AD WT group. The lack of endogenous AnxA1 also increased IgE relative to WT animals, demonstrating exacerbation of the allergic response. Histological analysis revealed intense eosinophilia and mast-cell activation in AD animals, especially in AnxA1^-/-. Both AD groups increased skin interleukin (IL)-13 levels, while IL-17A was upregulated in AnxA1^-/- lymph nodes and mast cells. High levels of phosphorylated ERK were detected in keratinocytes from AD groups. However, phospho-ERK levels were higher in the AnxA1^-/- when compared to the respective control groups. Our results suggest AnxA1 as an important therapeutic target for inflammatory skin diseases. Full article

(This article belongs to the Special Issue Mast Cells in Inflammation and Immunity)

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Review

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22 pages, 1126 KiB

Open AccessReview

The Role of Mast Cells in Stroke

by Edoardo Parrella, Vanessa Porrini, Marina Benarese and Marina Pizzi

Cells 2019, 8(5), 437; https://doi.org/10.3390/cells8050437 - 10 May 2019

Cited by 40 | Viewed by 5669

Abstract

Mast cells (MCs) are densely granulated perivascular resident cells of hematopoietic origin. Through the release of preformed mediators stored in their granules and newly synthesized molecules, they are able to initiate, modulate, and prolong the immune response upon activation. Their presence in the central nervous system (CNS) has been documented for more than a century. Over the years, MCs have been associated with various neuroinflammatory conditions of CNS, including stroke. They can exacerbate CNS damage in models of ischemic and hemorrhagic stroke by amplifying the inflammatory responses and promoting brain–blood barrier disruption, brain edema, extravasation, and hemorrhage. Here, we review the role of these peculiar cells in the pathophysiology of stroke, in both immature and adult brain. Further, we discuss the role of MCs as potential targets for the treatment of stroke and the compounds potentially active as MCs modulators. Full article

(This article belongs to the Special Issue Mast Cells in Inflammation and Immunity)

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24 pages, 1408 KiB

Open AccessReview

Intestinal Mucosal Mast Cells: Key Modulators of Barrier Function and Homeostasis

by Mercé Albert-Bayo, Irene Paracuellos, Ana M. González-Castro, Amanda Rodríguez-Urrutia, María J. Rodríguez-Lagunas, Carmen Alonso-Cotoner, Javier Santos and María Vicario

Cells 2019, 8(2), 135; https://doi.org/10.3390/cells8020135 - 08 Feb 2019

Cited by 117 | Viewed by 11269

Abstract

The gastrointestinal tract harbours the largest population of mast cells in the body; this highly specialised leukocyte cell type is able to adapt its phenotype and function to the microenvironment in which it resides. Mast cells react to external and internal stimuli thanks to the variety of receptors they express, and carry out effector and regulatory tasks by means of the mediators of different natures they produce. Mast cells are fundamental elements of the intestinal barrier as they regulate epithelial function and integrity, modulate both innate and adaptive mucosal immunity, and maintain neuro-immune interactions, which are key to functioning of the gut. Disruption of the intestinal barrier is associated with increased passage of luminal antigens into the mucosa, which further facilitates mucosal mast cell activation, inflammatory responses, and altered mast cell–enteric nerve interaction. Despite intensive research showing gut dysfunction to be associated with increased intestinal permeability and mucosal mast cell activation, the specific mechanisms linking mast cell activity with altered intestinal barrier in human disease remain unclear. This review describes the role played by mast cells in control of the intestinal mucosal barrier and their contribution to digestive diseases. Full article

(This article belongs to the Special Issue Mast Cells in Inflammation and Immunity)

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