Editorial

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Open AccessEditorial

The Role of Mast Cells and Their Inflammatory Mediators in Immunity

by Theoharis C. Theoharides

Int. J. Mol. Sci. 2023, 24(15), 12130; https://doi.org/10.3390/ijms241512130 - 28 Jul 2023

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Abstract

Mast cells have existed for almost 500 million years [...] Full article

(This article belongs to the Special Issue The Role of Mast Cells and Their Inflammatory Mediators in Immunity)

Research

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14 pages, 2929 KiB

Open AccessArticle

Amyloid Beta Peptides Lead to Mast Cell Activation in a Novel 3D Hydrogel Model

by Jingshu Liu, Sihan Liu, Li Zeng and Irene Tsilioni

Int. J. Mol. Sci. 2023, 24(15), 12002; https://doi.org/10.3390/ijms241512002 - 26 Jul 2023

Cited by 3 | Viewed by 1560

Abstract

Alzheimer’s disease (AD) is a prevalent neurodegenerative disease and the world’s primary cause of dementia among the elderly population. The aggregation of toxic amyloid-beta (Aβ) is one of the main pathological hallmarks of the AD brain. Recently, neuroinflammation has been recognized as one [...] Read more.

Alzheimer’s disease (AD) is a prevalent neurodegenerative disease and the world’s primary cause of dementia among the elderly population. The aggregation of toxic amyloid-beta (Aβ) is one of the main pathological hallmarks of the AD brain. Recently, neuroinflammation has been recognized as one of the major features of AD, which involves a network of interactions between immune cells. The mast cell (MC) is an innate immune cell type known to serve as a first responder to pathological changes and crosstalk with microglia and neurons. Although an increased number of mast cells were found near the sites of Aβ deposition, how mast cells are activated in AD is not clear. We developed a 3D culture system to culture MCs and investigated the activation of MCs by Aβ peptides. Because collagen I is the major component of extracellular matrix (ECM) in the brain, we encapsulated human LADR MCs in gels formed by collagen I. We found that 3D-cultured MCs survived and proliferated at the same level as MCs in suspension. Additionally, they can be induced to secrete inflammatory cytokines as well as MC proteases tryptase and chymase by typical MC activators interleukin 33 (IL-33) and IgE/anti-IgE. Culturing with peptides Aβ1-42, Aβ1-40, and Aβ25-35 caused MCs to secrete inflammatory mediators, with Aβ1-42 inducing the maximum level of activation. These data indicate that MCs respond to amyloid deposition to elicit inflammatory responses and demonstrate the validity of collagen gel as a model system to investigate MCs in a 3D environment to understand neuroinflammation in AD. Full article

(This article belongs to the Special Issue The Role of Mast Cells and Their Inflammatory Mediators in Immunity)

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10 pages, 1178 KiB

Open AccessCommunication

Recombinant SARS-CoV-2 Spike Protein Stimulates Secretion of Chymase, Tryptase, and IL-1β from Human Mast Cells, Augmented by IL-33

by Irene Tsilioni and Theoharis C. Theoharides

Int. J. Mol. Sci. 2023, 24(11), 9487; https://doi.org/10.3390/ijms24119487 - 30 May 2023

Cited by 6 | Viewed by 1458

Abstract

SARS-CoV-2 infects cells via its spike (S) protein binding to its surface receptor angiotensin-converting enzyme 2 (ACE2) and results in the production of multiple proinflammatory cytokines, especially in the lungs, leading to what is known as COVID-19. However, the cell source and the [...] Read more.

SARS-CoV-2 infects cells via its spike (S) protein binding to its surface receptor angiotensin-converting enzyme 2 (ACE2) and results in the production of multiple proinflammatory cytokines, especially in the lungs, leading to what is known as COVID-19. However, the cell source and the mechanism of secretion of such cytokines have not been adequately characterized. In this study, we used human cultured mast cells that are plentiful in the lungs and showed that recombinant SARS-CoV-2 full-length S protein (1–10 ng/mL), but not its receptor-binding domain (RBD), stimulates the secretion of the proinflammatory cytokine interleukin-1β (IL-1β) as well as the proteolytic enzymes chymase and tryptase. The secretion of IL-1β, chymase, and tryptase is augmented by the co-administration of interleukin-33 (IL-33) (30 ng/mL). This effect is mediated via toll-like receptor 4 (TLR4) for IL-1β and via ACE2 for chymase and tryptase. These results provide evidence that the SARS-CoV-2 S protein contributes to inflammation by stimulating mast cells through different receptors and could lead to new targeted treatment approaches. Full article

(This article belongs to the Special Issue The Role of Mast Cells and Their Inflammatory Mediators in Immunity)

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18 pages, 4842 KiB

Open AccessArticle

Lysophosphatidylinositol Promotes Chemotaxis and Cytokine Synthesis in Mast Cells with Differential Participation of GPR55 and CB2 Receptors

by Lizbeth Magnolia Martínez-Aguilar, Alfredo Ibarra-Sánchez, Daniel José Guerrero-Morán, Marina Macías-Silva, Jesús Omar Muñoz-Bello, Alejandro Padilla, Marcela Lizano and Claudia González-Espinosa

Int. J. Mol. Sci. 2023, 24(7), 6316; https://doi.org/10.3390/ijms24076316 - 28 Mar 2023

Cited by 2 | Viewed by 1724

Abstract

Mast cells (MCs) are the main participants in the control of immune reactions associated with inflammation, allergies, defense against pathogens, and tumor growth. Bioactive lipids are lipophilic compounds able to modulate MC activation. Here, we explored some of the effects of the bioactive [...] Read more.

Mast cells (MCs) are the main participants in the control of immune reactions associated with inflammation, allergies, defense against pathogens, and tumor growth. Bioactive lipids are lipophilic compounds able to modulate MC activation. Here, we explored some of the effects of the bioactive lipid lysophosphatidylinositol (LPI) on MCs. Utilizing murine bone marrow-derived mast cells (BMMCs), we found that LPI did not cause degranulation, but slightly increased FcεRI-dependent β-hexosaminidase release. However, LPI induced strong chemotaxis together with changes in LIM kinase (LIMK) and cofilin phosphorylation. LPI also promoted modifications to actin cytoskeleton dynamics that were detected by an increase in cell size and interruptions in the continuity of the cortical actin ring. The chemotaxis and cortical actin ring changes were dependent on GPR55 receptor activation, since the specific agonist O1602 mimicked the effects of LPI and the selective antagonist ML193 prevented them. The LPI and O1602-dependent stimulation of BMMC also led to VEGF, TNF, IL-1α, and IL-1β mRNA accumulation, but, in contrast with chemotaxis-related processes, the effects on cytokine transcription were dependent on GPR55 and cannabinoid (CB) 2 receptors, since they were sensitive to ML193 and to the specific CB2 receptor antagonist AM630. Remarkably, GPR55-dependent BMMC chemotaxis was observed towards conditioned media from distinct mouse and human cancer cells. Our data suggest that LPI induces the chemotaxis of MCs and leads to cytokine production in MC in vitro with the differential participation of GPR55 and CB2 receptors. These effects could play a significant role in the recruitment of MCs to tumors and the production of MC-derived pro-angiogenic factors in the tumor microenvironment. Full article

(This article belongs to the Special Issue The Role of Mast Cells and Their Inflammatory Mediators in Immunity)

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15 pages, 1098 KiB

Open AccessArticle

Quantitative Transcriptome Analysis of Purified Equine Mast Cells Identifies a Dominant Mucosal Mast Cell Population with Possible Inflammatory Functions in Airways of Asthmatic Horses

by Srinivas Akula, Miia Riihimäki, Ida Waern, Magnus Åbrink, Amanda Raine, Lars Hellman and Sara Wernersson

Int. J. Mol. Sci. 2022, 23(22), 13976; https://doi.org/10.3390/ijms232213976 - 12 Nov 2022

Cited by 4 | Viewed by 1880

Abstract

Asthma is a chronic inflammatory airway disease and a serious health problem in horses as well as in humans. In humans and mice, mast cells (MCs) are known to be directly involved in asthma pathology and subtypes of MCs accumulate in different lung [...] Read more.

Asthma is a chronic inflammatory airway disease and a serious health problem in horses as well as in humans. In humans and mice, mast cells (MCs) are known to be directly involved in asthma pathology and subtypes of MCs accumulate in different lung and airway compartments. The role and phenotype of MCs in equine asthma has not been well documented, although an accumulation of MCs in bronchoalveolar lavage fluid (BALF) is frequently seen. To characterize the phenotype of airway MCs in equine asthma we here developed a protocol, based on MACS Tyto sorting, resulting in the isolation of 92.9% pure MCs from horse BALF. We then used quantitative transcriptome analyses to determine the gene expression profile of the purified MCs compared with total BALF cells. We found that the MCs exhibited a protease profile typical for the classical mucosal MC subtype, as demonstrated by the expression of tryptase (TPSB2) alone, with no expression of chymase (CMA1) or carboxypeptidase A3 (CPA3). Moreover, the expression of genes involved in antigen presentation and complement activation strongly implicates an inflammatory role for these MCs. This study provides a first insight into the phenotype of equine MCs in BALF and their potential role in the airways of asthmatic horses. Full article

(This article belongs to the Special Issue The Role of Mast Cells and Their Inflammatory Mediators in Immunity)

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13 pages, 3077 KiB

Open AccessArticle

Inhibition of Complex I of the Respiratory Chain, but Not Complex III, Attenuates Degranulation and Cytokine Secretion in Human Skin Mast Cells

by Thomas Buttgereit, Moritz Pfeiffenberger, Stefan Frischbutter, Pierre-Louis Krauß, Yuling Chen, Marcus Maurer, Frank Buttgereit and Timo Gaber

Int. J. Mol. Sci. 2022, 23(19), 11591; https://doi.org/10.3390/ijms231911591 - 30 Sep 2022

Cited by 4 | Viewed by 1504

Abstract

The mechanisms of mast cell (MC) degranulation and MC-driven skin symptoms are well-described. In contrast, data about the role of mitochondrial respiration for immune functions of human skin MCs are lacking. Oxygen consumption rate (OCR) in primary human skin MCs during IgE-mediated activation [...] Read more.

The mechanisms of mast cell (MC) degranulation and MC-driven skin symptoms are well-described. In contrast, data about the role of mitochondrial respiration for immune functions of human skin MCs are lacking. Oxygen consumption rate (OCR) in primary human skin MCs during IgE-mediated activation in the absence of glucose was examined using a metabolic flux analyzer. Effects of the inhibition of mitochondrial complex I (by rotenone A) and III (by myxothiazol) on degranulation and cytokine secretion (IL-4, IL-5, IL-6, IL-13, TNF-α, and GM-CSF) were explored by the β-hexosaminidase release assay and multiplex ELISA. IgE-mediated activation rapidly increased the mitochondrial OCR and extracellular acidification; the contribution of non-mitochondrial oxygen consumption remained unchanged at lower levels. Both myxothiazol and rotenone A reduced OCR, the mitochondrial parameters, and extracellular acidification; however, myxothiazol did not affect degranulation and cytokine secretion. In contrast, degranulation and the secretion of IL-6, IL-13, TNF-α, and GM-CSF were reduced by rotenone A, whereas the secretion of IL-4 and IL-5 was not significantly affected. The inhibitors did not affect cell viability. Our results highlight the important role played by mitochondrial respiration in primary human skin MCs and allow for a conclusion on a hierarchy of their effector functions. Drugs targeting specific pathways in mitochondria may provide future options to control MC-driven skin symptoms. Full article

(This article belongs to the Special Issue The Role of Mast Cells and Their Inflammatory Mediators in Immunity)

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Review

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18 pages, 1393 KiB

Open AccessReview

Potential Role of Moesin in Regulating Mast Cell Secretion

by Theoharis C. Theoharides and Duraisamy Kempuraj

Int. J. Mol. Sci. 2023, 24(15), 12081; https://doi.org/10.3390/ijms241512081 - 28 Jul 2023

Cited by 2 | Viewed by 1657

Abstract

Mast cells have existed for millions of years in species that never suffer from allergic reactions. Hence, in addition to allergies, mast cells can play a critical role in homeostasis and inflammation via secretion of numerous vasoactive, pro-inflammatory and neuro-sensitizing mediators. Secretion may [...] Read more.

Mast cells have existed for millions of years in species that never suffer from allergic reactions. Hence, in addition to allergies, mast cells can play a critical role in homeostasis and inflammation via secretion of numerous vasoactive, pro-inflammatory and neuro-sensitizing mediators. Secretion may utilize different modes that involve the cytoskeleton, but our understanding of the molecular mechanisms regulating secretion is still not well understood. The Ezrin/Radixin/Moesin (ERM) family of proteins is involved in linking cell surface-initiated signaling to the actin cytoskeleton. However, how ERMs may regulate secretion from mast cells is still poorly understood. ERMs contain two functional domains connected through a long α-helix region, the N-terminal FERM (band 4.1 protein-ERM) domain and the C-terminal ERM association domain (C-ERMAD). The FERM domain and the C-ERMAD can bind to each other in a head-to-tail manner, leading to a closed/inactive conformation. Typically, phosphorylation on the C-terminus Thr has been associated with the activation of ERMs, including secretion from macrophages and platelets. It has previously been shown that the ability of the so-called mast cell “stabilizer” disodium cromoglycate (cromolyn) to inhibit secretion from rat mast cells closely paralleled the phosphorylation of a 78 kDa protein, which was subsequently shown to be moesin, a member of ERMs. Interestingly, the phosphorylation of moesin during the inhibition of mast cell secretion was on the N-terminal Ser56/74 and Thr66 residues. This phosphorylation pattern could lock moesin in its inactive state and render it inaccessible to binding to the Soluble NSF attachment protein receptors (SNAREs) and synaptosomal-associated proteins (SNAPs) critical for exocytosis. Using confocal microscopic imaging, we showed moesin was found to colocalize with actin and cluster around secretory granules during inhibition of secretion. In conclusion, the phosphorylation pattern and localization of moesin may be important in the regulation of mast cell secretion and could be targeted for the development of effective inhibitors of secretion of allergic and inflammatory mediators from mast cells. Full article

(This article belongs to the Special Issue The Role of Mast Cells and Their Inflammatory Mediators in Immunity)

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14 pages, 1033 KiB

Open AccessReview

Mast Cells and Interleukins

by Antonio Giovanni Solimando, Vanessa Desantis and Domenico Ribatti

Int. J. Mol. Sci. 2022, 23(22), 14004; https://doi.org/10.3390/ijms232214004 - 13 Nov 2022

Cited by 14 | Viewed by 3860

Abstract

Mast cells play a critical role in inflammatory diseases and tumor growth. The versatility of mast cells is reflected in their ability to secrete a wide range of biologically active cytokines, including interleukins, chemokines, lipid mediators, proteases, and biogenic amines. The aim of [...] Read more.

Mast cells play a critical role in inflammatory diseases and tumor growth. The versatility of mast cells is reflected in their ability to secrete a wide range of biologically active cytokines, including interleukins, chemokines, lipid mediators, proteases, and biogenic amines. The aim of this review article is to analyze the complex involvement of mast cells in the secretion of interleukins and the role of interleukins in the regulation of biological activities of mast cells. Full article

(This article belongs to the Special Issue The Role of Mast Cells and Their Inflammatory Mediators in Immunity)

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Other

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18 pages, 4606 KiB

Open AccessBrief Report

KIT D816V Mast Cells Derived from Induced Pluripotent Stem Cells Recapitulate Systemic Mastocytosis Transcriptional Profile

by Marcelo A. S. de Toledo, Xuhuang Fu, Tiago Maié, Eva M. Buhl, Katrin Götz, Susanne Schmitz, Anne Kaiser, Peter Boor, Till Braunschweig, Nicolas Chatain, Ivan G. Costa, Tim H. Brümmendorf, Steffen Koschmieder and Martin Zenke

Int. J. Mol. Sci. 2023, 24(6), 5275; https://doi.org/10.3390/ijms24065275 - 09 Mar 2023

Cited by 6 | Viewed by 2142

Abstract

Mast cells (MCs) represent a population of hematopoietic cells with a key role in innate and adaptive immunity and are well known for their detrimental role in allergic responses. Yet, MCs occur in low abundance, which hampers their detailed molecular analysis. Here, we [...] Read more.

Mast cells (MCs) represent a population of hematopoietic cells with a key role in innate and adaptive immunity and are well known for their detrimental role in allergic responses. Yet, MCs occur in low abundance, which hampers their detailed molecular analysis. Here, we capitalized on the potential of induced pluripotent stem (iPS) cells to give rise to all cells in the body and established a novel and robust protocol for human iPS cell differentiation toward MCs. Relying on a panel of systemic mastocytosis (SM) patient-specific iPS cell lines carrying the KIT D816V mutation, we generated functional MCs that recapitulate SM disease features: increased number of MCs, abnormal maturation kinetics and activated phenotype, CD25 and CD30 surface expression and a transcriptional signature characterized by upregulated expression of innate and inflammatory response genes. Therefore, human iPS cell-derived MCs are a reliable, inexhaustible, and close-to-human tool for disease modeling and pharmacological screening to explore novel MC therapeutics. Full article

(This article belongs to the Special Issue The Role of Mast Cells and Their Inflammatory Mediators in Immunity)

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