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Biomolecules
Special Issues
Molecular Basis of Mast Cells Activation and Medical Implications
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Molecular Basis of Mast Cells Activation and Medical Implications

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Biological Factors".

Deadline for manuscript submissions: 31 July 2026 | Viewed by 7747

Special Issue Editors

Dr. Grzegorz Porebski

E-Mail Website
Guest Editor
Department of Clinical and Environmental Allergology, Jagiellonian University Medical College, 31-503 Krakow, Poland
Interests: mast cell; immediate hypersensitivity; drug allergy; hereditary angioedema; C1 inhibitor deficiency
Dr. Matija Rijavec

E-Mail Website
Guest Editor
Laboratory for Clinical Immunology and Molecular Genetics, University Clinic of Respiratory and Allergic Diseases, 4204 Golnik, Slovenia
Interests: basophils; Hymenoptera venom anaphylaxis; mast cell disorders; hereditary alpha-tryptasemia; hereditary angioedema
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Mast cells respond to environmental cues and inflammatory signals. This response translates into complex roles in immunity, tissue homeostasis, and diseases, particularly allergy and hypersensitivity reactions. They are activated through various receptors, including the high-affinity IgE receptor, cytokine receptors, and pattern recognition receptors. Subsequently, intracellular signaling pathways and calcium signaling events lead to mast cell degranulation, mediator release, and the development of a wide range of immediate hypersensitivity medical conditions, from local urticaria to anaphylaxis.

Over the last decade, significant progress has been made in understanding mast cell activation and the regulation mechanisms that may be involved in the development and progression of allergy and hypersensitivity reactions.

The aim of this Special Issue is to highlight recent advances in this field, which may be useful in the prevention of individuals of developing immediate hypersensitivity reactions and in the development of pharmacotherapeutic strategies through the evaluation of novel effective molecular targets.

We encourage researchers who are interested in this topic to submit original research articles that highlight the current preclinical and clinical knowledge on the molecular basis of mast cell activation and implications for the development of mast-cell-driven allergy and hypersensitivity reactions. In addition, critical and systematic review articles covering the relevant research, with concluding remarks and suggestions for future work, will also be considered for inclusion in this Special Issue.

Dr. Grzegorz Porebski
Dr. Matija Rijavec
Guest Editors

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 250 words) can be sent to the Editorial Office for assessment.

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. Biomolecules is an international peer-reviewed open access monthly 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

  • mast cells
  • allergy
  • immediate hypersensitivity
  • molecular mechanisms

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Published Papers (4 papers)

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Research

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14 pages, 2001 KB  
Article
Icatibant Acts as a Balanced Ligand of MRGPRX2 in Human Skin Mast Cells
by Zhuoran Li, Jean Schneikert, Gürkan Bal, Torsten Zuberbier and Magda Babina
Biomolecules 2025, 15(9), 1224; https://doi.org/10.3390/biom15091224 - 25 Aug 2025
Cited by 2 | Viewed by 2473
Abstract
MRGPRX2 (Mas-related G protein-coupled receptor member X2) is implicated in mast cell (MC)-driven disorders due to its ability to bind diverse ligands, which may be G-protein-biased or balanced, with the latter activating both G-proteins and the β-arrestin pathway. Icatibant, a peptide drug, produces [...] Read more.
MRGPRX2 (Mas-related G protein-coupled receptor member X2) is implicated in mast cell (MC)-driven disorders due to its ability to bind diverse ligands, which may be G-protein-biased or balanced, with the latter activating both G-proteins and the β-arrestin pathway. Icatibant, a peptide drug, produces injection-site reactions in most patients and is used experimentally to probe MRGPRX2 function in skin tests. While reported to be G-protein-biased, it is unknown how skin MCs respond to icatibant, although these are the primary target cells during therapy. We therefore compared responses to icatibant with those induced by the balanced agonist substance P (SP) in skin MCs. Degranulation and desensitization were assessed via β-hexosaminidase release, receptor internalization by flow cytometry, and downstream signaling by immunoblotting. Skin MCs degranulated in response to SP and icatibant, relying on Gi proteins and calcium channels; Gq and PI3K (Phosphoinositide 3-kinase) contributed more strongly to exocytosis following icatibant, while JNK (c-Jun n-terminal kinase) was more relevant for SP. Both agonists activated ERK, PI3K/AKT, and (weakly) p38. Surprisingly, and in contrast to the LAD2 (Laboratory of Allergic Diseases 2 mast cell line) MC line, icatibant was at least as potent as SP in eliciting MRGPRX2 internalization and (cross-)desensitization in skin MCs. These findings suggest that icatibant functions differently in primary versus transformed MCs, acting as a fully balanced ligand in the former by triggering not only degranulation but also receptor internalization and desensitization. Therefore, not only the ligand but also the MRGPRX2-expressing cell plays a decisive role in whether a ligand is balanced or biased. These findings are relevant to our understanding of icatibant’s clinical effects on edema and itch. Full article
(This article belongs to the Special Issue Molecular Basis of Mast Cells Activation and Medical Implications)
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Review

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25 pages, 919 KB  
Review
Mast Cells and Substance P: Neuroinflammatory Loops at the Molecular and Translational Clinical Levels
by Ernesto Aitella, Marilena Bruno, Gianluca Azzellino, Massimo De Martinis, Lia Ginaldi and Ciro Romano
Biomolecules 2026, 16(4), 539; https://doi.org/10.3390/biom16040539 - 4 Apr 2026
Viewed by 1140
Abstract
Mast cells, characterized by a broad repertoire of surface receptors, are increasingly recognized for activation pathways extending beyond the classical IgE/FcεRI axis, particularly in the context of neurogenic inflammation. Substance P (SP), a neuropeptide of the tachykinin family, is a potent activator of [...] Read more.
Mast cells, characterized by a broad repertoire of surface receptors, are increasingly recognized for activation pathways extending beyond the classical IgE/FcεRI axis, particularly in the context of neurogenic inflammation. Substance P (SP), a neuropeptide of the tachykinin family, is a potent activator of mast cells, inducing the release of histamine, cytokines, and other inflammatory mediators. Through complex bidirectional communication, mast cells and SP play a pivotal role in neuro–immune interactions. This narrative review provides an updated overview of mast cell–SP crosstalk, with a focus on underlying molecular mechanisms, receptor-mediated signaling pathways, and their contribution to pathophysiological processes. In addition, we aim to reinterpret established clinical models within the spectrum of pseudoallergic conditions and to explore innovative, etiology-driven therapeutic strategies. Finally, we discuss future perspectives and highlight the need for robust translational models to support clinical and pharmacological research. Full article
(This article belongs to the Special Issue Molecular Basis of Mast Cells Activation and Medical Implications)
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20 pages, 654 KB  
Review
Role of Mast Cells and Neuroinflammation in Neuropsychiatric Disorders of the Developmental Period
by Ernesto Aitella, Ludovico Neri, Gianluca Azzellino, Ciro Romano, Massimo De Martinis, Rita Roncone and Lia Ginaldi
Biomolecules 2026, 16(4), 530; https://doi.org/10.3390/biom16040530 - 2 Apr 2026
Viewed by 1627
Abstract
Mast cells can release different kinds of molecules as a response to different stimuli, particularly proinflammatory mediators that contribute to neuroinflammation. The enrichment of mast cells in specific areas of the nervous system and gastrointestinal tract, together with their degranulation, histamine and neuropeptide [...] Read more.
Mast cells can release different kinds of molecules as a response to different stimuli, particularly proinflammatory mediators that contribute to neuroinflammation. The enrichment of mast cells in specific areas of the nervous system and gastrointestinal tract, together with their degranulation, histamine and neuropeptide secretion, such as substance P, and mast cell–microglia interactions, may promote neuroinflammatory signaling in neurological and psychiatric disorders during childhood and adolescence. The aim of this review is to explore the mast cell-related molecular aspects of the main neuropsychiatric disorders of the developmental period, such as ADHD, autism spectrum disorder, and epilepsy, as well as anxiety and depression. The translational analysis of molecular pathways and the relationships involved may contribute to the development of innovative and targeted therapeutic approaches. Full article
(This article belongs to the Special Issue Molecular Basis of Mast Cells Activation and Medical Implications)
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21 pages, 995 KB  
Review
The Gut Microbiota–Mast Cell Axis in Intestinal Homeostasis and Food Allergy Pathogenesis
by Alessia Carnevale, Caterina Marangio, Erisa Putro, Rosa Molfetta and Rossella Paolini
Biomolecules 2026, 16(2), 254; https://doi.org/10.3390/biom16020254 - 5 Feb 2026
Viewed by 1629
Abstract
Food allergy is an increasing global health burden, particularly in industrialized countries, with rising prevalence in both pediatric and adult populations. It is characterized by exaggerated immune responses to innocuous dietary antigens, leading to clinical manifestations ranging from mild gastrointestinal symptoms to life-threatening [...] Read more.
Food allergy is an increasing global health burden, particularly in industrialized countries, with rising prevalence in both pediatric and adult populations. It is characterized by exaggerated immune responses to innocuous dietary antigens, leading to clinical manifestations ranging from mild gastrointestinal symptoms to life-threatening anaphylaxis. Mast cells are central effectors in the pathophysiology of food allergy, initiating and amplifying allergic inflammation through the release of a broad array of mediators upon activation. Recent studies have revealed that the intestinal microbiota plays a critical role in shaping immune responses, including the regulation of mast cell development, maturation, and activation. Moreover, dysbiosis has been associated with increased susceptibility to allergic sensitization and heightened mast cell reactivity. This review explores the molecular mechanisms underlying the microbiota–mast cell axis in the context of intestinal homeostasis and food allergy with a particular emphasis on the regulation of mast cell effector functions by TLR signaling and microbial metabolites. We also discuss the therapeutic potential of targeting the microbiota–mast cell axis as novel strategies to restore immune tolerance. Understanding this complex crosstalk opens new avenues for translational approaches in the prevention and treatment of food allergy. Full article
(This article belongs to the Special Issue Molecular Basis of Mast Cells Activation and Medical Implications)
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