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24 pages, 12458 KiB

Open AccessArticle

Human Mast Cells Upregulate Cathepsin B, a Novel Marker of Itch in Psoriasis

by Peter W. West, Chiara Tontini, Haris Atmoko, Orsolya Kiss, Terence Garner, Rajia Bahri, Richard B. Warren, Christopher E. M. Griffiths, Adam Stevens and Silvia Bulfone-Paus

Cells 2023, 12(17), 2177; https://doi.org/10.3390/cells12172177 - 30 Aug 2023

Viewed by 1488

Abstract

Mast cells (MCs) contribute to skin inflammation. In psoriasis, the activation of cutaneous neuroimmune networks commonly leads to itch. To dissect the unique contribution of MCs to the cutaneous neuroinflammatory response in psoriasis, we examined their density, distribution, relation to nerve fibres and [...] Read more.

Mast cells (MCs) contribute to skin inflammation. In psoriasis, the activation of cutaneous neuroimmune networks commonly leads to itch. To dissect the unique contribution of MCs to the cutaneous neuroinflammatory response in psoriasis, we examined their density, distribution, relation to nerve fibres and disease severity, and molecular signature by comparing RNA-seq analysis of MCs isolated from the skin of psoriasis patients and healthy volunteers. In involved psoriasis skin, MCs and Calcitonin Gene-Related Peptide (CGRP)-positive nerve fibres were spatially associated, and the increase of both MC and nerve fibre density correlated with disease severity. Gene set enrichment analysis of differentially expressed genes in involved psoriasis skin showed significant representation of neuron-related pathways (i.e., regulation of neuron projection along with dendrite and dendritic spine morphogenesis), indicating MC engagement in neuronal development and supporting the evidence of close MC–nerve fibre interaction. Furthermore, the analysis of 208 identified itch-associated genes revealed that CTSB, TLR4, and TACR1 were upregulated in MCs in involved skin. In both whole-skin published datasets and isolated MCs, CTSB was found to be a reliable indicator of the psoriasis condition. Furthermore, cathepsin B+ cells were increased in psoriasis skin and cathepsin B+ MC density correlated with disease severity. Therefore, our study provides evidence that cathepsin B could serve as a common indicator of the MC-dependent itch signature in psoriasis. Full article

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

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15 pages, 3001 KiB

Open AccessArticle

IRF3 Activation in Mast Cells Promotes FcεRI-Mediated Allergic Inflammation

by Young-Ae Choi, Hima Dhakal, Soyoung Lee, Namkyung Kim, Byungheon Lee, Taeg Kyu Kwon, Dongwoo Khang and Sang-Hyun Kim

Cells 2023, 12(11), 1493; https://doi.org/10.3390/cells12111493 - 28 May 2023

Viewed by 1579

Abstract

(1) Background: This study aims to elucidate a novel non-transcriptional action of IRF3 in addition to its role as a transcription factor in mast cell activation and associated allergic inflammation; (2) Methods: For in vitro experiments, mouse bone-marrow-derived mast cells (mBMMCs) and a [...] Read more.

(1) Background: This study aims to elucidate a novel non-transcriptional action of IRF3 in addition to its role as a transcription factor in mast cell activation and associated allergic inflammation; (2) Methods: For in vitro experiments, mouse bone-marrow-derived mast cells (mBMMCs) and a rat basophilic leukemia cell line (RBL-2H3) were used for investigating the underlying mechanism of IRF3 in mast-cell-mediated allergic inflammation. For in vivo experiments, wild-type and Irf3 knockout mice were used for evaluating IgE-mediated local and systemic anaphylaxis; (3) Results: Passive cutaneous anaphylaxis (PCA)-induced tissues showed highly increased IRF3 activity. In addition, the activation of IRF3 was observed in DNP-HSA-treated mast cells. Phosphorylated IRF3 by DNP-HSA was spatially co-localized with tryptase according to the mast cell activation process, and FcεRI-mediated signaling pathways directly regulated that activity. The alteration of IRF3 affected the production of granule contents in the mast cells and the anaphylaxis responses, including PCA- and ovalbumin-induced active systemic anaphylaxis. Furthermore, IRF3 influenced the post-translational processing of histidine decarboxylase (HDC), which is required for granule maturation; and (4) Conclusion: Through this study, we demonstrated the novel function of IRF3 as an important factor inducing mast cell activation and as an upstream molecule for HDC activity. Full article

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

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16 pages, 2657 KiB

Open AccessArticle

Mast Cell Tryptase Promotes Airway Remodeling by Inducing Anti-Apoptotic and Cell Growth Properties in Human Alveolar and Bronchial Epithelial Cells

by Frida Berlin, Sofia Mogren, Camilla Ly, Sangeetha Ramu, Morten Hvidtfeldt, Lena Uller, Celeste Porsbjerg and Cecilia K. Andersson

Cells 2023, 12(10), 1439; https://doi.org/10.3390/cells12101439 - 22 May 2023

Cited by 2 | Viewed by 1505

Abstract

Bronchial and alveolar remodeling and impaired epithelial function are characteristics of chronic respiratory diseases. In these patients, an increased number of mast cells (MCs) positive for serine proteases, tryptase and chymase, infiltrate the epithelium and alveolar parenchyma. However, little is known regarding the [...] Read more.

Bronchial and alveolar remodeling and impaired epithelial function are characteristics of chronic respiratory diseases. In these patients, an increased number of mast cells (MCs) positive for serine proteases, tryptase and chymase, infiltrate the epithelium and alveolar parenchyma. However, little is known regarding the implication of intraepithelial MCs on the local environment, such as epithelial cell function and properties. In this study, we investigated whether MC tryptase is involved in bronchial and alveolar remodeling and the mechanisms of regulation during inflammation. Using novel holographic live cell imaging, we found that MC tryptase enhanced human bronchial and alveolar epithelial cell growth and shortened the cell division intervals. The elevated cell growth induced by tryptase remained in a pro-inflammatory state. Tryptase also increased the expression of the anti-apoptotic protein BIRC3, as well as growth factor release in epithelial cells. Thus, our data imply that the intraepithelial and alveolar MC release of tryptase may play a critical role in disturbing bronchial epithelial and alveolar homeostasis by altering cell growth–death regulation. Full article

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

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17 pages, 2469 KiB

Open AccessArticle

Clorfl86/RHEX Is a Negative Regulator of SCF/KIT Signaling in Human Skin Mast Cells

by Kristin Franke, Gürkan Bal, Zhuoran Li, Torsten Zuberbier and Magda Babina

Cells 2023, 12(9), 1306; https://doi.org/10.3390/cells12091306 - 3 May 2023

Cited by 4 | Viewed by 1592

Abstract

Mast cells (MCs) are key effector cells in allergic and inflammatory diseases, and the SCF/KIT axis regulates most aspects of the cells’ biology. Using terminally differentiated skin MCs, we recently reported on proteome-wide phosphorylation changes initiated by KIT dimerization. C1orf186/RHEX was revealed as [...] Read more.

Mast cells (MCs) are key effector cells in allergic and inflammatory diseases, and the SCF/KIT axis regulates most aspects of the cells’ biology. Using terminally differentiated skin MCs, we recently reported on proteome-wide phosphorylation changes initiated by KIT dimerization. C1orf186/RHEX was revealed as one of the proteins to become heavily phosphorylated. Its function in MCs is undefined and only some information is available for erythroblasts. Using public databases and our own data, we now report that RHEX exhibits highly restricted expression with a clear dominance in MCs. While expression is most pronounced in mature MCs, RHEX is also abundant in immature/transformed MC cell lines (HMC-1, LAD2), suggesting early expression with further increase during differentiation. Using RHEX-selective RNA interference, we reveal that RHEX unexpectedly acts as a negative regulator of SCF-supported skin MC survival. This finding is substantiated by RHEX’s interference with KIT signal transduction, whereby ERK1/2 and p38 both were more strongly activated when RHEX was attenuated. Comparing RHEX and capicua (a recently identified repressor) revealed that each protein preferentially suppresses other signaling modules elicited by KIT. Induction of immediate-early genes strictly requires ERK1/2 in SCF-triggered MCs; we now demonstrate that RHEX diminution translates to this downstream event, and thereby enhances NR4A2, JUNB, and EGR1 induction. Collectively, our study reveals RHEX as a repressor of KIT signaling and function in MCs. As an abundant and selective lineage marker, RHEX may have various roles in the lineage, and the provided framework will enable future work on its involvement in other crucial processes. Full article

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

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21 pages, 5414 KiB

Open AccessArticle

GEF-H1 Transduces FcεRI Signaling in Mast Cells to Activate RhoA and Focal Adhesion Formation during Exocytosis

by Yitian Guo, Judeah Negre and Gary Eitzen

Cells 2023, 12(4), 537; https://doi.org/10.3390/cells12040537 - 7 Feb 2023

Cited by 1 | Viewed by 1470

Abstract

When antigen-stimulated, mast cells release preformed inflammatory mediators stored in cytoplasmic granules. This occurs via a robust exocytosis mechanism termed degranulation. Our previous studies revealed that RhoA and Rac1 are activated during mast cell antigen stimulation and are required for mediator release. Here, [...] Read more.

When antigen-stimulated, mast cells release preformed inflammatory mediators stored in cytoplasmic granules. This occurs via a robust exocytosis mechanism termed degranulation. Our previous studies revealed that RhoA and Rac1 are activated during mast cell antigen stimulation and are required for mediator release. Here, we show that the RhoGEF, GEF-H1, acts as a signal transducer of antigen stimulation to activate RhoA and promote mast cell spreading via focal adhesion (FA) formation. Cell spreading, granule movement, and exocytosis were all reduced in antigen-stimulated mast cells when GEF-H1 was depleted by RNA interference. GEF-H1-depleted cells also showed a significant reduction in RhoA activation, resulting in reduced stress fiber formation without altering lamellipodia formation. Ectopic expression of a constitutively active RhoA mutant restored normal morphology in GEF-H1-depleted cells. FA formation during antigen stimulation required GEF-H1, suggesting it is a downstream target of the GEF-H1-RhoA signaling axis. GEF-H1 was activated by phosphorylation in conjunction with antigen stimulation. Syk kinase is linked to the FcεRI signaling pathway and the Syk inhibitor, GS-9973, blocked GEF-H1 activation and also suppressed cell spreading, granule movement, and exocytosis. We concluded that during FcεRI receptor stimulation, GEF-H1 transmits signals to RhoA activation and FA formation to facilitate the exocytosis mechanism. Full article

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

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15 pages, 2839 KiB

Open AccessArticle

Thalidomide Attenuates Mast Cell Activation by Upregulating SHP-1 Signaling and Interfering with the Action of CRBN

by Hyeun-Wook Chang, Kyeong-Hwa Sim and Youn-Ju Lee

Cells 2023, 12(3), 469; https://doi.org/10.3390/cells12030469 - 1 Feb 2023

Cited by 2 | Viewed by 1922

Abstract

Allergy is a chronic inflammatory disease, and its incidence has increased worldwide in recent years. Thalidomide, which was initially used as an anti-emetic drug but was withdrawn due to its teratogenic effects, is now used to treat blood cancers. Although the anti-inflammatory and [...] Read more.

Allergy is a chronic inflammatory disease, and its incidence has increased worldwide in recent years. Thalidomide, which was initially used as an anti-emetic drug but was withdrawn due to its teratogenic effects, is now used to treat blood cancers. Although the anti-inflammatory and immunomodulatory properties of thalidomide have been reported, little is known about its influence on the mast cell-mediated allergic reaction. In the present study, we aimed to evaluate the anti-allergic activity of thalidomide and the underlying mechanism using mouse bone marrow-derived mast cells (BMMCs) and passive cutaneous anaphylaxis (PCA) mouse models. Thalidomide markedly decreased the degranulation and release of lipid mediators and cytokines in IgE/Ag-stimulated BMMCs, with concurrent inhibition of FcεRI-mediated positive signaling pathways including Syk and activation of negative signaling pathways including AMP-activated protein kinase (AMPK) and SH2 tyrosine phosphatase-1 (SHP-1). The knockdown of AMPK or SHP-1 with specific siRNA diminished the inhibitory effects of thalidomide on BMMC activation. By contrast, the knockdown of cereblon (CRBN), which is the primary target protein of thalidomide, augmented the effects of thalidomide. Thalidomide reduced the interactions of CRBN with Syk and AMPK promoted by FcεRI crosslinking, thereby relieving the suppression of AMPK signaling and suppressing Syk signaling. Furthermore, oral thalidomide treatment suppressed the PCA reaction in mice. In conclusion, thalidomide suppresses FcεRI-mediated mast cell activation by activating the AMPK and SHP-1 pathways and antagonizing the action of CRBN, indicating that it is a potential anti-allergic agent. Full article

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

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Review

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17 pages, 2854 KiB

Open AccessReview

Degranulation of Mast Cells as a Target for Drug Development

by Bo-Gie Yang, A-Ram Kim, Dajeong Lee, Seong Beom An, Yaein Amy Shim and Myoung Ho Jang

Cells 2023, 12(11), 1506; https://doi.org/10.3390/cells12111506 - 29 May 2023

Cited by 7 | Viewed by 4304

Abstract

Mast cells act as key effector cells of inflammatory responses through degranulation. Mast cell degranulation is induced by the activation of cell surface receptors, such as FcεRI, MRGPRX2/B2, and P2RX7. Each receptor, except FcεRI, varies in its expression pattern depending on the tissue, [...] Read more.

Mast cells act as key effector cells of inflammatory responses through degranulation. Mast cell degranulation is induced by the activation of cell surface receptors, such as FcεRI, MRGPRX2/B2, and P2RX7. Each receptor, except FcεRI, varies in its expression pattern depending on the tissue, which contributes to their differing involvement in inflammatory responses depending on the site of occurrence. Focusing on the mechanism of allergic inflammatory responses by mast cells, this review will describe newly identified mast cell receptors in terms of their involvement in degranulation induction and patterns of tissue-specific expression. In addition, new drugs targeting mast cell degranulation for the treatment of allergy-related diseases will be introduced. Full article

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

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20 pages, 1620 KiB

Open AccessReview

Mast Cells as a Target—A Comprehensive Review of Recent Therapeutic Approaches

by Joanna Baran, Anna Sobiepanek, Anna Mazurkiewicz-Pisarek, Marta Rogalska, Aleksander Gryciuk, Lukasz Kuryk, Soman N. Abraham and Monika Staniszewska

Cells 2023, 12(8), 1187; https://doi.org/10.3390/cells12081187 - 19 Apr 2023

Cited by 9 | Viewed by 4970

Abstract

Mast cells (MCs) are the immune cells distributed throughout nearly all tissues, mainly in the skin, near blood vessels and lymph vessels, nerves, lungs, and the intestines. Although MCs are essential to the healthy immune response, their overactivity and pathological states can lead [...] Read more.

Mast cells (MCs) are the immune cells distributed throughout nearly all tissues, mainly in the skin, near blood vessels and lymph vessels, nerves, lungs, and the intestines. Although MCs are essential to the healthy immune response, their overactivity and pathological states can lead to numerous health hazards. The side effect of mast cell activity is usually caused by degranulation. It can be triggered by immunological factors, such as immunoglobulins, lymphocytes, or antigen–antibody complexes, and non-immune factors, such as radiation and pathogens. An intensive reaction of mast cells can even lead to anaphylaxis, one of the most life-threatening allergic reactions. What is more, mast cells play a role in the tumor microenvironment by modulating various events of tumor biology, such as cell proliferation and survival, angiogenesis, invasiveness, and metastasis. The mechanisms of the mast cell actions are still poorly understood, making it difficult to develop therapies for their pathological condition. This review focuses on the possible therapies targeting mast cell degranulation, anaphylaxis, and MC-derived tumors. Full article

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

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