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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 August 2022) | Viewed by 44772

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Dr. Giovanna Traina

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Department of Pharmaceutical Sciences, University of Perugia, Via Romana, 06126 Perugia, Italy
Interests: inflammation; neuroinflammation; gut-brain axis; mast cells; learning and memory
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Increasing evidence suggests that mast cells play a crucial role in human health and diseases.

Mast cells are known to be involved cells in allergic reactions through degranulation and the release of a variety of mediators with vasoactive, inflammatory, and nociceptive activities. Mast cells are sensors of the environment, able to respond promptly and selectively. Mast cells are intriguing and multifactorial cells and play a leading role in various pathological conditions.

The localization of mast cells within the tissue and their expression of specific mediators such as chymases or tryptases is important evidence from the diagnostic point of view. Chronic inflammation is a common mediator of various disorders which include many pathological conditions, pain, migraine, depression, anxiety, autoimmune diseases, fibromyalgia, but also Alzheimer’s disease, multiple sclerosis, atherosclerosis, and cardiovascular diseases. Modulation of the hyperactivity of mast cells and the reduction of the release of inflammatory factors could constitute a new frontier of therapeutic intervention aimed at preventing chronic inflammation.

Topics:

New developments in mast cell management in human disorders
New molecular insights in mast cell control
Mast cells and microbiome
Mast cells and nociception
Mast cells and food allergy
Mast cells and neuroinflammation
Mast cells and stress

Dr. Giovanna Traina
Guest Editor

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Keywords

mast cells
human diseases
pain
cardiovascular diseases
microbiome
food allergy
stress
cancer

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Published Papers (11 papers)

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Editorial

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3 pages, 170 KiB

Open AccessEditorial

Mast Cells in Human Health and Diseases

by Giovanna Traina

Int. J. Mol. Sci. 2023, 24(7), 6668; https://doi.org/10.3390/ijms24076668 - 3 Apr 2023

Cited by 2 | Viewed by 1296

Abstract

This Special Issue includes articles that discuss several important aspects regarding the role of mast cells (MCs) and elucidate some cellular and molecular mechanisms of these multifaceted cells [...] Full article

(This article belongs to the Special Issue Mast Cells in Human Health and Diseases)

Research

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13 pages, 6184 KiB

Open AccessArticle

The Distinct Effects of the Mitochondria-Targeted STAT3 Inhibitors Mitocur-1 and Mitocur-3 on Mast Cell and Mitochondrial Functions

by Anastasia N. Pavlyuchenkova, Maria A. Chelombitko, Artem V. Fedorov, Maria K. Kuznetsova, Roman A. Zinovkin and Ehud Razin

Int. J. Mol. Sci. 2023, 24(2), 1471; https://doi.org/10.3390/ijms24021471 - 12 Jan 2023

Cited by 6 | Viewed by 2068

Abstract

There is accumulating evidence that mitochondria and mitochondrial STAT3 are involved in the activation of mast cells. The mitochondria-targeted curcuminoids Mitocur-1 and Mitocur-3 have been suggested to reduce antigen-dependent mast cell activation by inhibiting mitochondrial STAT3. The aim of the current work was to investigate the mechanisms of action of these mitocurcuminoids on mast cells and mitochondrial functions. The pretreatment of rat basophilic leukemia cells RBL-2H3 with Mitocur-1 and Mitocur-3 decreased antigen-dependent degranulation but did not affect spontaneous degranulation. Both compounds caused mitochondrial fragmentation and increased mitochondrial ROS. Inhibition of Drp1 prevented mitochondrial fragmentation induced by Mitocur-3 but not by Mitocur-1. The antioxidant N-acetylcysteine inhibited mitochondrial fission induced by Mitocur-1 but not Mitocur-3. Mitochondrial fragmentation caused by Mitocur-3 but not Mitocur-1 was accompanied by activation of Drp1 and AMPK. These data suggest a distinct mechanism of action of mitocurcuminoids on the mitochondria of RBL-2H3 cells: Mitocur-3 stimulated AMPK and caused Drp1-dependent mitochondrial fragmentation, while Mitocur-1-induced mitochondrial fission was ROS-dependent. This difference may contribute to the higher toxicity of Mitocur-3 compared to Mitocur-1. The findings contribute to further drug development for inflammatory and allergic diseases. Full article

(This article belongs to the Special Issue Mast Cells in Human Health and Diseases)

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11 pages, 1400 KiB

Open AccessArticle

Increased NMUR1 Expression in Mast Cells in the Synovial Membrane of Obese Osteoarthritis Patients

by Ayumi Tsukada, Ken Takata, Shotaro Takano, Yoshihisa Ohashi, Manabu Mukai, Jun Aikawa, Dai Iwase, Gen Inoue, Masashi Takaso and Kentaro Uchida

Int. J. Mol. Sci. 2022, 23(19), 11237; https://doi.org/10.3390/ijms231911237 - 23 Sep 2022

Cited by 8 | Viewed by 1776

Abstract

Obesity is a risk factor for knee osteoarthritis (KOA). Neuromedin U (NMU) and NMU receptors (NMUR1 and NMUR2) are associated with obesity-related disorders and found in mast cells (MCs), which are elevated in osteoarthritis. However, NMU/NMUR expression was not examined in the synovial membrane (SM) or synovial MCs of obese osteoarthritis patients. We compared expression of NMU, NMUR1, NMUR2, and the mast cell (MC) marker, CPA3, in the SM of KOA patients categorized as normal weight (NW; BMI < 25 kg/m², n = 79), overweight (OW; BMI ≥ 25 and <30 kg/m², n = 87), and obese (OB; ≥30 kg/m², n = 40). To study NMU/NMUR expression in MCs, we compared the MC-rich fraction (MC-RF), CD88(+) MC-RF, and CD88(−) MC-RF, extracted using magnetic isolation, with the MC-poor fraction (MC-PF). While NMU and NMUR2 expression were comparable, NMUR1 was significantly elevated in OW and OB compared to NW. Moreover, CPA3 levels were significantly greater in OB than NW. NMUR1 and CPA3 expression were significantly higher in both the CD88(+) and CD88(−) MC-RF than MC-PF. Therefore, NMUR1 expression was elevated in the SM of OB KOA patients, and its expression was found in MCs. Further investigation to analyze the NMU/NMUR1 pathway in MC may provide a link between obesity and KOA pathology. Full article

(This article belongs to the Special Issue Mast Cells in Human Health and Diseases)

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11 pages, 8041 KiB

Open AccessArticle

The Heat Shock Protein 90 (HSP90) Is Required for the IL-33-Induced Cytokine Production in Mast Cells (MCs)

by Isabel Peters, Sylvia Müller, Claudia Küchler, Ute Jäger and Sebastian Drube

Int. J. Mol. Sci. 2022, 23(18), 10855; https://doi.org/10.3390/ijms231810855 - 17 Sep 2022

Cited by 4 | Viewed by 2009

Abstract

The alarmin interleukin-33 (IL-33) is released upon cell stress and damage in peripheral tissues. The receptor for IL-33 is the Toll/Interleukin-1 receptor (TIR)-family member T1/ST2 (the IL-33R), which is highly and constitutively expressed on MCs. The sensing of IL-33 by MCs induces the MyD88−TAK1−IKK2-dependent activation of p65/RelA and MAP-kinases, which mediate the production of pro-inflammatory cytokines and amplify FcεRI-mediated MC-effector functions and the resulting allergic reactions. Therefore, the investigation of IL-33-induced signaling is of interest for developing therapeutic interventions effective against allergic reactions. Importantly, beside the release of IL-33, heat shock proteins (HSPs) are upregulated during allergic reactions. This maintains the biological functions of signaling molecules and/or cytokines but unfortunately also strengthens the severity of inflammatory reactions. Here, we demonstrate that HSP90 does not support the IL-33-induced and MyD88−TAK1−IKK2-dependent activation of p65/RelA and of mitogen-activated protein (MAP)-kinases. We found that HSP90 acts downstream of these signaling pathways, mediates the stability of produced cytokine mRNAs, and therefore facilitates the resulting cytokine production. These data show that IL-33 enables MCs to perform an effective cytokine production by the upregulation of HSP90. Consequently, HSP90 might be an attractive therapeutic target for blocking IL-33-mediated inflammatory reactions. Full article

(This article belongs to the Special Issue Mast Cells in Human Health and Diseases)

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14 pages, 2273 KiB

Open AccessArticle

Substance P Serves as a Balanced Agonist for MRGPRX2 and a Single Tyrosine Residue Is Required for β-Arrestin Recruitment and Receptor Internalization

by Chalatip Chompunud Na Ayudhya, Aetas Amponnawarat and Hydar Ali

Int. J. Mol. Sci. 2021, 22(10), 5318; https://doi.org/10.3390/ijms22105318 - 18 May 2021

Cited by 24 | Viewed by 4004

Abstract

The neuropeptide substance P (SP) mediates neurogenic inflammation and pain and contributes to atopic dermatitis in mice through the activation of mast cells (MCs) via Mas-related G protein-coupled receptor (GPCR)-B2 (MrgprB2, human ortholog MRGPRX2). In addition to G proteins, certain MRGPRX2 agonists activate an additional signaling pathway that involves the recruitment of β-arrestins, which contributes to receptor internalization and desensitization (balanced agonists). We found that SP caused β-arrestin recruitment, MRGPRX2 internalization, and desensitization. These responses were independent of G proteins, indicating that SP serves as a balanced agonist for MRGPRX2. A tyrosine residue in the highly conserved NPxxY motif contributes to the activation and internalization of many GPCRs. We have previously shown that Tyr²⁷⁹ of MRGPRX2 is essential for G protein-mediated signaling and degranulation. To assess its role in β-arrestin-mediated MRGPRX2 regulation, we replaced Tyr²⁷⁹ in the NPxxY motif of MRGPRX2 with Ala (Y279A). Surprisingly, we found that, unlike the wild-type receptor, Y279A mutant of MRGPRX2 was resistant to SP-induced β-arrestin recruitment and internalization. This study reveals the novel findings that activation of MRGPRX2 by SP is regulated by β-arrestins and that a highly conserved tyrosine residue within MRGPRX2’s NPxxY motif contributes to both G protein- and β-arrestin-mediated responses. Full article

(This article belongs to the Special Issue Mast Cells in Human Health and Diseases)

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Review

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19 pages, 1248 KiB

Open AccessReview

Exploring Mast Cell–CD8 T Cell Interactions in Inflammatory Skin Diseases

by Yiqiao Chen, Christopher E. M. Griffiths and Silvia Bulfone-Paus

Int. J. Mol. Sci. 2023, 24(2), 1564; https://doi.org/10.3390/ijms24021564 - 13 Jan 2023

Cited by 11 | Viewed by 3881

Abstract

The skin is exposed to environmental challenges and contains skin-resident immune cells, including mast cells (MCs) and CD8 T cells that act as sentinels for pathogens and environmental antigens. Human skin MCs and their mediators participate in the maintenance of tissue homeostasis and regulate the recruitment and activity of immune cells involved in the pathogenesis of skin diseases. The cutaneous CD8 T cell compartment is comprised of long-persisting resident memory T cells (T_RM) and migratory or recirculating cells; both populations provide durable site immune surveillance. Several lines of evidence indicate that MC-derived products, such as CCL5 and TNF-α, modulate the migration and function of CD8 T cells. Conversely, activated CD8 T cells induce the upregulation of MC costimulatory molecules. Moreover, the close apposition of MCs and CD8 T cells has been recently identified in the skin of several dermatoses, such as alopecia areata. This review outlines the current knowledge about bidirectional interactions between human MCs and CD8 T cells, analyses the alteration of their communication in the context of three common skin disorders in which these cells have been found altered in number or function—psoriasis, atopic dermatitis, and vitiligo—and discusses the current unanswered questions. Full article

(This article belongs to the Special Issue Mast Cells in Human Health and Diseases)

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18 pages, 1525 KiB

Open AccessReview

Mast Cells and Dendritic Cells as Cellular Immune Checkpoints in Immunotherapy of Solid Tumors

by Katerina Kalkusova, Sindija Smite, Elea Darras, Pavla Taborska, Dmitry Stakheev, Luca Vannucci, Jirina Bartunkova and Daniel Smrz

Int. J. Mol. Sci. 2022, 23(19), 11080; https://doi.org/10.3390/ijms231911080 - 21 Sep 2022

Cited by 8 | Viewed by 2955

Abstract

The immune checkpoint inhibitors have revolutionized cancer immunotherapy. These inhibitors are game changers in many cancers and for many patients, sometimes show unprecedented therapeutic efficacy. However, their therapeutic efficacy is largely limited in many solid tumors where the tumor-controlled immune microenvironment prevents the immune system from efficiently reaching, recognizing, and eliminating cancer cells. The tumor immune microenvironment is largely orchestrated by immune cells through which tumors gain resistance against the immune system. Among these cells are mast cells and dendritic cells. Both cell types possess enormous capabilities to shape the immune microenvironment. These capabilities stage these cells as cellular checkpoints in the immune microenvironment. Regaining control over these cells in the tumor microenvironment can open new avenues for breaking the resistance of solid tumors to immunotherapy. In this review, we will discuss mast cells and dendritic cells in the context of solid tumors and how these immune cells can, alone or in cooperation, modulate the solid tumor resistance to the immune system. We will also discuss how this modulation could be used in novel immunotherapeutic modalities to weaken the solid tumor resistance to the immune system. This weakening could then help other immunotherapeutic modalities engage against these tumors more efficiently. Full article

(This article belongs to the Special Issue Mast Cells in Human Health and Diseases)

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31 pages, 5829 KiB

Open AccessReview

The Multifaceted Roles of Mast Cells in Immune Homeostasis, Infections and Cancers

by Anna Sobiepanek, Łukasz Kuryk, Mariangela Garofalo, Sandeep Kumar, Joanna Baran, Paulina Musolf, Frank Siebenhaar, Joachim Wilhelm Fluhr, Tomasz Kobiela, Roberto Plasenzotti, Karl Kuchler and Monika Staniszewska

Int. J. Mol. Sci. 2022, 23(4), 2249; https://doi.org/10.3390/ijms23042249 - 17 Feb 2022

Cited by 25 | Viewed by 5307

Abstract

Mast cells (MCs) play important roles in normal immune responses and pathological states. The location of MCs on the boundaries between tissues and the external environment, including gut mucosal surfaces, lungs, skin, and around blood vessels, suggests a multitude of immunological functions. Thus, MCs are pivotal for host defense against different antigens, including allergens and microbial pathogens. MCs can produce and respond to physiological mediators and chemokines to modulate inflammation. As long-lived, tissue-resident cells, MCs indeed mediate acute inflammatory responses such as those evident in allergic reactions. Furthermore, MCs participate in innate and adaptive immune responses to bacteria, viruses, fungi, and parasites. The control of MC activation or stabilization is a powerful tool in regulating tissue homeostasis and pathogen clearance. Moreover, MCs contribute to maintaining the homeostatic equilibrium between host and resident microbiota, and they engage in crosstalk between the resident and recruited hematopoietic cells. In this review, we provide a comprehensive overview of the functions of MCs in health and disease. Further, we discuss how mouse models of MC deficiency have become useful tools for establishing MCs as a potential cellular target for treating inflammatory disorders. Full article

(This article belongs to the Special Issue Mast Cells in Human Health and Diseases)

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24 pages, 2023 KiB

Open AccessReview

Mastocytosis and Mast Cell Activation Disorders: Clearing the Air

by Clayton Webster Jackson, Cristina Marie Pratt, Chase Preston Rupprecht, Debendra Pattanaik and Guha Krishnaswamy

Int. J. Mol. Sci. 2021, 22(20), 11270; https://doi.org/10.3390/ijms222011270 - 19 Oct 2021

Cited by 33 | Viewed by 10996

Abstract

Mast cells are derived from hematopoietic stem cell precursors and are essential to the genesis and manifestations of the allergic response. Activation of these cells by allergens leads to degranulation and elaboration of inflammatory mediators, responsible for regulating the acute dramatic inflammatory response seen. Mast cells have also been incriminated in such diverse disorders as malignancy, arthritis, coronary artery disease, and osteoporosis. There has been a recent explosion in our understanding of the mast cell and the associated clinical conditions that affect this cell type. Some mast cell disorders are associated with specific genetic mutations (such as the D816V gain-of-function mutation) with resultant clonal disease. Such disorders include cutaneous mastocytosis, systemic mastocytosis (SM), its variants (indolent/ISM, smoldering/SSM, aggressive systemic mastocytosis/ASM) and clonal (or monoclonal) mast cell activation disorders or syndromes (CMCAS/MMAS). Besides clonal mast cell activations disorders/CMCAS (also referred to as monoclonal mast cell activation syndromes/MMAS), mast cell activation can also occur secondary to allergic, inflammatory, or paraneoplastic disease. Some disorders are idiopathic as their molecular pathogenesis and evolution are unclear. A genetic disorder, referred to as hereditary alpha-tryptasemia (H

α

T) has also been described recently. This condition has been shown to be associated with increased severity of allergic and anaphylactic reactions and may interact variably with primary and secondary mast cell disease, resulting in complex combined disorders. The role of this review is to clarify the classification of mast cell disorders, point to molecular aspects of mast cell signaling, elucidate underlying genetic defects, and provide approaches to targeted therapies that may benefit such patients. Full article

(This article belongs to the Special Issue Mast Cells in Human Health and Diseases)

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12 pages, 901 KiB

Open AccessReview

Extracellular Vesicles as Emerging Players in Intercellular Communication: Relevance in Mast Cell-Mediated Pathophysiology

by Irit Shefler, Pazit Salamon and Yoseph A. Mekori

Int. J. Mol. Sci. 2021, 22(17), 9176; https://doi.org/10.3390/ijms22179176 - 25 Aug 2021

Cited by 18 | Viewed by 3268

Abstract

Mast cells are major effector cells in eliciting allergic responses. They also play a significant role in establishing innate and adaptive immune responses, as well as in modulating tumor growth. Mast cells can be activated upon engagement of the high-affinity receptor FcεRI with specific IgE to multivalent antigens or in response to several FcεRI-independent mechanisms. Upon stimulation, mast cells secrete various preformed and newly synthesized mediators. Emerging evidence indicates their ability to be a rich source of secreted extracellular vesicles (EVs), including exosomes and microvesicles, which convey biological functions. Mast cell-derived EVs can interact with and affect other cells located nearby or at distant sites and modulate inflammation, allergic response, and tumor progression. Mast cells are also affected by EVs derived from other cells in the immune system or in the tumor microenvironment, which may activate mast cells to release different mediators. In this review, we summarize the latest data regarding the ability of mast cells to release or respond to EVs and their role in allergic responses, inflammation, and tumor progression. Understanding the release, composition, and uptake of EVs by cells located near to or at sites distant from mast cells in a variety of clinical conditions, such as allergic inflammation, mastocytosis, and lung cancer will contribute to developing novel therapeutic approaches. Full article

(This article belongs to the Special Issue Mast Cells in Human Health and Diseases)

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14 pages, 876 KiB

Open AccessReview

Effects of Primary Mast Cell Disease on Hemostasis and Erythropoiesis

by Holger Seidel, Hans-Jörg Hertfelder, Johannes Oldenburg, Johannes P. Kruppenbacher, Lawrence B. Afrin and Gerhard J. Molderings

Int. J. Mol. Sci. 2021, 22(16), 8960; https://doi.org/10.3390/ijms22168960 - 20 Aug 2021

Cited by 12 | Viewed by 4198

Abstract

Mast cell disease is an epigenetically and genetically determined disease entity with very diverse clinical manifestations in potentially every system and tissue due to inap pro priate release of variable subsets of mast cell mediators together with accumulation of either morphologically normal or altered mast cells. Easy bruising, excessive bleeding, and aberrancies of erythropoiesis can frequently be observed in patients with mast cell disease. A thorough history, including a family history, will guide the appropriate work-up, and laboratory evaluations may provide clues to diagnosis. In recent years, our understanding of the involvement of coagulation and anticoagulant pathways, the fibrinolytic system, and erythropoiesis in the pathophysiology of mast cell disease has increased considerably. This review summarizes current knowledge of the impact of the disturbed hemostatic and erythropoietic balance in patients with mast cell disease and describes options of treatment. Full article

(This article belongs to the Special Issue Mast Cells in Human Health and Diseases)

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