International Journal of Molecular Sciences

Editorial

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11 pages, 656 KiB

Open AccessEditorial

Mast Cells: Fascinating but Still Elusive after 140 Years from Their Discovery

by Gilda Varricchi and Gianni Marone

Int. J. Mol. Sci. 2020, 21(2), 464; https://doi.org/10.3390/ijms21020464 - 11 Jan 2020

Cited by 23 | Viewed by 4201

Abstract

Some of the basic characteristics of tissue mast cells were described over 140 years ago by Paul Ehrlich, the founder of modern immunology [...] Full article

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

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Research

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12 pages, 1034 KiB

Open AccessArticle

Aldh2 Attenuates Stem Cell Factor/Kit-Dependent Signaling and Activation in Mast Cells

by Do-Kyun Kim, Young-Eun Cho, Byoung-Joon Song, Toshihiro Kawamoto, Dean D. Metcalfe and Ana Olivera

Int. J. Mol. Sci. 2019, 20(24), 6216; https://doi.org/10.3390/ijms20246216 - 10 Dec 2019

Cited by 3 | Viewed by 2910

Abstract

Mitochondrial aldehyde dehydrogenase (ALDH2) metabolizes endogenous and exogenous aldehydes and protects cells against oxidative injury. Inactivating genetic polymorphisms in humans are common and associate with alcohol flush reactions. However, whether mast cell Aldh2 activity impacts normal mast cell responses is unknown. Using bone [...] Read more.

Mitochondrial aldehyde dehydrogenase (ALDH2) metabolizes endogenous and exogenous aldehydes and protects cells against oxidative injury. Inactivating genetic polymorphisms in humans are common and associate with alcohol flush reactions. However, whether mast cell Aldh2 activity impacts normal mast cell responses is unknown. Using bone marrow-derived mast cells from Aldh2 knockout mice, we found evidence for a role of mast cell Aldh2 in Kit-mediated responses. Aldh2-deficient mast cells showed enhanced Kit tyrosine kinase phosphorylation and activity after stimulation with its ligand (stem cell factor) and augmentation of downstream signaling pathways, including Stat4, MAPKs, and Akt. The activity of the phosphatase Shp-1, which attenuates Kit activity, was reduced in Aldh2^−/− mast cells, along with an increase in reactive oxygen species, known to regulate Shp-1. Reduced Shp-1 activity concomitant with sustained Kit signaling resulted in greater proliferation following Kit engagement, and increased mediator and cytokine release when Aldh2^−/− mast cells were co-stimulated via Kit and FcεRI. However, FcεRI-mediated signaling and responses were unaffected. Therefore, our findings reveal a functional role for mast cell intrinsic Aldh2 in the control of Kit activation and Kit-mediated responses, which may lead to a better understanding of mast cell reactivity in conditions related to ALDH2 polymorphisms. Full article

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

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9 pages, 3125 KiB

Open AccessCommunication

Description and Characterization of a Novel Human Mast Cell Line for Scientific Study

by Arnold S. Kirshenbaum, Yuzhi Yin, J. Bruce Sundstrom, Geethani Bandara and Dean D. Metcalfe

Int. J. Mol. Sci. 2019, 20(22), 5520; https://doi.org/10.3390/ijms20225520 - 06 Nov 2019

Cited by 23 | Viewed by 4752

Abstract

Background: Laboratory of allergic diseases 2 (LAD2) human mast cells were developed over 15 years ago and have been distributed worldwide for studying mast cell proliferation, receptor expression, mediator release/inhibition, and signaling. LAD2 cells were derived from CD34+ cells following marrow aspiration of [...] Read more.

Background: Laboratory of allergic diseases 2 (LAD2) human mast cells were developed over 15 years ago and have been distributed worldwide for studying mast cell proliferation, receptor expression, mediator release/inhibition, and signaling. LAD2 cells were derived from CD34+ cells following marrow aspiration of a patient with aggressive mastocytosis with no identified mutations in KIT. Another aspiration gave rise to a second cell line which has recently been re-established (LADR). We queried whether LADR had unique properties for the preclinical study of human mast cell biology. Methods: LADR and LAD2 cells were cultured under identical conditions. Experiments examined proliferation, beta-hexosaminidase (β-hex) release, surface receptor and granular protease expression, infectivity with HIV, and gene expression. Results: LADR cells were larger and more granulated as seen with Wright–Giemsa staining and flow cytometry, with cell numbers doubling in 4 weeks, in contrast to LAD2 cells, which doubled every 2 weeks. Both LADR and LAD2 cells released granular contents following aggregation of FcεRI. LADR cells showed log-fold increases in FcεRI/CD117 and expressed CD13, CD33, CD34, CD63, CD117, CD123, CD133, CD184, CD193, and CD195, while LAD2 cells expressed CD33, CD34, CD63, CD117, CD133, CD193 but not CD13, CD123, CD184, or CD195. LADR tryptase expression was one-log-fold increased. LADR cell and LAD2 cell chymase expression were similar. Both cell lines could be infected with T-tropic, M-tropic, and dual tropic HIV. Following monomeric human IgE stimulation, LADR cells showed greater surface receptor and mRNA expression for CD184 and CD195. Expression arrays revealed differences in gene upregulation, especially for the suppressor of cytokine signaling (SOCS) family of genes with their role in JAK2/STAT3 signaling and cellular myelocytomatosis oncogene (c-MYC) in cell growth and regulation. Conclusions: LADR cells are thus unique in that they exhibit a slower proliferation rate, are more advanced in development, have increased FcεRI/CD117 and tryptase expression, have a different profile of gene expression, and show earlier infectivity with HIV-BAL, LAV, and TYBE when compared to LAD2 cells. This new cell line is thus a valuable addition to the few FcεRI+ human mast cell lines previously described and available for scientific inquiry. Full article

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

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13 pages, 1857 KiB

Open AccessArticle

Lipocalin 2: A New Antimicrobial in Mast Cells

by Yu-Ling Chang, Zhenping Wang, Satomi Igawa, Jae Eun Choi, Tyler Werbel and Anna Di Nardo

Int. J. Mol. Sci. 2019, 20(10), 2380; https://doi.org/10.3390/ijms20102380 - 14 May 2019

Cited by 12 | Viewed by 3552

Abstract

Mast cells (MCs) play a significant role in the innate immune defense against bacterial infection through the release of cytokines and antimicrobial peptides. However, their antimicrobial function is still only partially described. We therefore hypothesized that MCs express additional antimicrobial peptides. In this [...] Read more.

Mast cells (MCs) play a significant role in the innate immune defense against bacterial infection through the release of cytokines and antimicrobial peptides. However, their antimicrobial function is still only partially described. We therefore hypothesized that MCs express additional antimicrobial peptides. In this study, we used FANTOM 5 transcriptome data to identify for the first time that MCs express lipocalin 2 (LCN2), a known inhibitor of bacterial growth. Using MCs derived from mice which were deficient in LCN2, we showed that this antimicrobial peptide is an important component of the MCs’ antimicrobial activity against Escherichia coli (E. coli). Since sphingosine-1-phosphate receptors (S1PRs) on MCs are known to regulate their function during infections, we hypothesized that S1P could activate LCN2 production in MCs. Using an in vitro assay, we demonstrated that S1P enhances MCs antimicrobial peptide production and increases the capacity of MCs to directly kill S. aureus and E. coli via an LCN2 release. In conclusion, we showed that LCN2 is expressed by MCs and plays a role in their capacity to inhibit bacterial growth. Full article

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

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15 pages, 1959 KiB

Open AccessArticle

Tetrahydrocannabinol Reduces Hapten-Driven Mast Cell Accumulation and Persistent Tactile Sensitivity in Mouse Model of Allergen-Provoked Localized Vulvodynia

by Beebie Boo, Rohit Kamath, Erica Arriaga-Gomez, Jasmine Landry, Elizabeth Emanuel, Sookyong Joo, Marietta Saldías Montivero, Tijana Martinov, Brian T. Fife and Devavani Chatterjea

Int. J. Mol. Sci. 2019, 20(9), 2163; https://doi.org/10.3390/ijms20092163 - 01 May 2019

Cited by 11 | Viewed by 4199

Abstract

Vulvodynia is a remarkably prevalent chronic pain condition of unknown etiology. An increase in numbers of vulvar mast cells often accompanies a clinical diagnosis of vulvodynia and a history of allergies amplifies the risk of developing this condition. We previously showed that repeated [...] Read more.

Vulvodynia is a remarkably prevalent chronic pain condition of unknown etiology. An increase in numbers of vulvar mast cells often accompanies a clinical diagnosis of vulvodynia and a history of allergies amplifies the risk of developing this condition. We previously showed that repeated exposures to oxazolone dissolved in ethanol on the labiar skin of mice led to persistent genital sensitivity to pressure and a sustained increase in labiar mast cells. Here we sensitized female mice to the hapten dinitrofluorobenzene (DNFB) dissolved in saline on their flanks, and subsequently challenged them with the same hapten or saline vehicle alone for ten consecutive days either on labiar skin or in the vaginal canal. We evaluated tactile ano-genital sensitivity, and tissue inflammation at serial timepoints. DNFB-challenged mice developed significant, persistent tactile sensitivity. Allergic sites showed mast cell accumulation, infiltration of resident memory CD8⁺CD103⁺ T cells, early, localized increases in eosinophils and neutrophils, and sustained elevation of serum Immunoglobulin E (IgE). Therapeutic intra-vaginal administration of Δ⁹-tetrahydrocannabinol (THC) reduced mast cell accumulation and tactile sensitivity. Mast cell-targeted therapeutic strategies may therefore provide new ways to manage and treat vulvar pain potentially instigated by repeated allergenic exposures. Full article

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

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15 pages, 1588 KiB

Open AccessArticle

A Transcriptomic Insight into the Impact of Colon Cancer Cells on Mast Cells

by Yingxin Yu, Bart R. Blokhuis, Johan Garssen and Frank A. Redegeld

Int. J. Mol. Sci. 2019, 20(7), 1689; https://doi.org/10.3390/ijms20071689 - 04 Apr 2019

Cited by 9 | Viewed by 3132

Abstract

Mast cells (MCs) are one of the first immune cells recruited to a tumor. It is well recognized that MCs accumulate in colon cancer lesion and their density is associated with the clinical outcomes. However, the molecular mechanism of how colon cancer cells [...] Read more.

Mast cells (MCs) are one of the first immune cells recruited to a tumor. It is well recognized that MCs accumulate in colon cancer lesion and their density is associated with the clinical outcomes. However, the molecular mechanism of how colon cancer cells may modify MC function is still unclear. In this study, primary human MCs were generated from CD34⁺ progenitor cells and a 3D coculture model was developed to study the interplay between colon cancer cells and MCs. By comparing the transcriptomic profile of colon cancer-cocultured MCs versus control MCs, we identified a number of deregulated genes, such as MMP-2, VEGF-A, PDGF-A, COX2, NOTCH1 and ISG15, which contribute to the enrichment of cancer-related pathways. Intriguingly, pre-stimulation with a TLR2 agonist prior to colon cancer coculture induced upregulation of multiple interferon-inducible genes as well as MHC molecules in MCs. Our study provides an alternative approach to study the influence of colon cancer on MCs. The transcriptome signature of colon cancer-cocultured MCs may potentially reflect the mechanism of how colon cancer cells educate MCs to become pro-tumorigenic in the initial phase and how a subsequent inflammatory signal—e.g., TLR2 ligands—may modify their responses in the cancer milieu. Full article

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

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Review

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23 pages, 2581 KiB

Open AccessReview

Mast Cells as Potential Accelerators of Human Atherosclerosis—From Early to Late Lesions

by Petri T. Kovanen

Int. J. Mol. Sci. 2019, 20(18), 4479; https://doi.org/10.3390/ijms20184479 - 11 Sep 2019

Cited by 48 | Viewed by 4899

Abstract

Mast cells are present in atherosclerotic lesions throughout their progression. The process of atherogenesis itself is characterized by infiltration and retention of cholesterol-containing blood-derived low-density lipoprotein (LDL) particles in the intimal layer of the arterial wall, where the particles become modified and ingested [...] Read more.

Mast cells are present in atherosclerotic lesions throughout their progression. The process of atherogenesis itself is characterized by infiltration and retention of cholesterol-containing blood-derived low-density lipoprotein (LDL) particles in the intimal layer of the arterial wall, where the particles become modified and ingested by macrophages, resulting in the formation of cholesterol-filled foam cells. Provided the blood-derived high-density lipoproteins (HDL) particles are able to efficiently carry cholesterol from the foam cells back to the circulation, the early lesions may stay stable or even disappear. However, the modified LDL particles also trigger a permanent local inflammatory reaction characterized by the presence of activated macrophages, T cells, and mast cells, which drive lesion progression. Then, the HDL particles become modified and unable to remove cholesterol from the foam cells. Ultimately, the aging foam cells die and form a necrotic lipid core. In such advanced lesions, the lipid core is separated from the circulating blood by a collagenous cap, which may become thin and fragile and susceptible to rupture, so causing an acute atherothrombotic event. Regarding the potential contribution of mast cells in the initiation and progression of atherosclerotic lesions, immunohistochemical studies in autopsied human subjects and studies in cell culture systems and in atherosclerotic mouse models have collectively provided evidence that the compounds released by activated mast cells may promote atherogenesis at various steps along the path of lesion development. This review focuses on the presence of activated mast cells in human atherosclerotic lesions. Moreover, some of the molecular mechanisms potentially governing activation and effector functions of mast cells in such lesions are presented and discussed. Full article

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

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23 pages, 1470 KiB

Open AccessReview

Immune and Inflammatory Cells in Thyroid Cancer Microenvironment

by Silvia Martina Ferrari, Poupak Fallahi, Maria Rosaria Galdiero, Ilaria Ruffilli, Giusy Elia, Francesca Ragusa, Sabrina Rosaria Paparo, Armando Patrizio, Valeria Mazzi, Gilda Varricchi, Gianni Marone and Alessandro Antonelli

Int. J. Mol. Sci. 2019, 20(18), 4413; https://doi.org/10.3390/ijms20184413 - 07 Sep 2019

Cited by 133 | Viewed by 8798

Abstract

A hallmark of cancer is the ability of tumor cells to avoid immune destruction. Activated immune cells in tumor microenvironment (TME) secrete proinflammatory cytokines and chemokines which foster the proliferation of tumor cells. Specific antigens expressed by cancer cells are recognized by the [...] Read more.

A hallmark of cancer is the ability of tumor cells to avoid immune destruction. Activated immune cells in tumor microenvironment (TME) secrete proinflammatory cytokines and chemokines which foster the proliferation of tumor cells. Specific antigens expressed by cancer cells are recognized by the main actors of immune response that are involved in their elimination (immunosurveillance). By the recruitment of immunosuppressive cells, decreasing the tumor immunogenicity, or through other immunosuppressive mechanisms, tumors can impair the host immune cells within the TME and escape their surveillance. Within the TME, cells of the innate (e.g., macrophages, mast cells, neutrophils) and the adaptive (e.g., lymphocytes) immune responses are interconnected with epithelial cancer cells, fibroblasts, and endothelial cells via cytokines, chemokines, and adipocytokines. The molecular pattern of cytokines and chemokines has a key role and could explain the involvement of the immune system in tumor initiation and progression. Thyroid cancer-related inflammation is an important target for diagnostic procedures and novel therapeutic strategies. Anticancer immunotherapy, especially immune checkpoint inhibitors, unleashes the immune system and activates cytotoxic lymphocytes to kill cancer cells. A better knowledge of the molecular and immunological characteristics of TME will allow novel and more effective immunotherapeutic strategies in advanced thyroid cancer. Full article

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

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25 pages, 1981 KiB

Open AccessReview

Future Needs in Mast Cell Biology

by Gilda Varricchi, Amato de Paulis, Gianni Marone and Stephen J. Galli

Int. J. Mol. Sci. 2019, 20(18), 4397; https://doi.org/10.3390/ijms20184397 - 06 Sep 2019

Cited by 83 | Viewed by 8229

Abstract

The pathophysiological roles of mast cells are still not fully understood, over 140 years since their description by Paul Ehrlich in 1878. Initial studies have attempted to identify distinct “subpopulations” of mast cells based on a relatively small number of biochemical characteristics. More [...] Read more.

The pathophysiological roles of mast cells are still not fully understood, over 140 years since their description by Paul Ehrlich in 1878. Initial studies have attempted to identify distinct “subpopulations” of mast cells based on a relatively small number of biochemical characteristics. More recently, “subtypes” of mast cells have been described based on the analysis of transcriptomes of anatomically distinct mouse mast cell populations. Although mast cells can potently alter homeostasis, in certain circumstances, these cells can also contribute to the restoration of homeostasis. Both solid and hematologic tumors are associated with the accumulation of peritumoral and/or intratumoral mast cells, suggesting that these cells can help to promote and/or limit tumorigenesis. We suggest that at least two major subsets of mast cells, MC1 (meaning anti-tumorigenic) and MC2 (meaning pro-tumorigenic), and/or different mast cell mediators derived from otherwise similar cells, could play distinct or even opposite roles in tumorigenesis. Mast cells are also strategically located in the human myocardium, in atherosclerotic plaques, in close proximity to nerves and in the aortic valve. Recent studies have revealed evidence that cardiac mast cells can participate both in physiological and pathological processes in the heart. It seems likely that different subsets of mast cells, like those of cardiac macrophages, can exert distinct, even opposite, effects in different pathophysiological processes in the heart. In this chapter, we have commented on possible future needs of the ongoing efforts to identify the diverse functions of mast cells in health and disease. Full article

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

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18 pages, 891 KiB

Open AccessReview

Mast Cell Responses to Viruses and Pathogen Products

by Jean S. Marshall, Liliana Portales-Cervantes and Edwin Leong

Int. J. Mol. Sci. 2019, 20(17), 4241; https://doi.org/10.3390/ijms20174241 - 30 Aug 2019

Cited by 111 | Viewed by 7213

Abstract

Mast cells are well accepted as important sentinel cells for host defence against selected pathogens. Their location at mucosal surfaces and ability to mobilize multiple aspects of early immune responses makes them critical contributors to effective immunity in several experimental settings. However, the [...] Read more.

Mast cells are well accepted as important sentinel cells for host defence against selected pathogens. Their location at mucosal surfaces and ability to mobilize multiple aspects of early immune responses makes them critical contributors to effective immunity in several experimental settings. However, the interactions of mast cells with viruses and pathogen products are complex and can have both detrimental and positive impacts. There is substantial evidence for mast cell mobilization and activation of effector cells and mobilization of dendritic cells following viral challenge. These cells are a major and under-appreciated local source of type I and III interferons following viral challenge. However, mast cells have also been implicated in inappropriate inflammatory responses, long term fibrosis, and vascular leakage associated with viral infections. Progress in combating infection and boosting effective immunity requires a better understanding of mast cell responses to viral infection and the pathogen products and receptors we can employ to modify such responses. In this review, we outline some of the key known responses of mast cells to viral infection and their major responses to pathogen products. We have placed an emphasis on data obtained from human mast cells and aim to provide a framework for considering the complex interactions between mast cells and pathogens with a view to exploiting this knowledge therapeutically. Long-lived resident mast cells and their responses to viruses and pathogen products provide excellent opportunities to modify local immune responses that remain to be fully exploited in cancer immunotherapy, vaccination, and treatment of infectious diseases. Full article

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

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15 pages, 454 KiB

Open AccessReview

Mast Cells, Stress, Fear and Autism Spectrum Disorder

by Theoharis C. Theoharides, Maria Kavalioti and Irene Tsilioni

Int. J. Mol. Sci. 2019, 20(15), 3611; https://doi.org/10.3390/ijms20153611 - 24 Jul 2019

Cited by 31 | Viewed by 11180

Abstract

Autism Spectrum Disorder (ASD) is a developmental condition characterized by impaired communication and obsessive behavior that affects 1 in 59 children. ASD is expected to affect 1 in about 40 children by 2020, but there is still no distinct pathogenesis or effective treatments. [...] Read more.

Autism Spectrum Disorder (ASD) is a developmental condition characterized by impaired communication and obsessive behavior that affects 1 in 59 children. ASD is expected to affect 1 in about 40 children by 2020, but there is still no distinct pathogenesis or effective treatments. Prenatal stress has been associated with higher risk of developing ASD in the offspring. Moreover, children with ASD cannot handle anxiety and respond disproportionately even to otherwise benign triggers. Stress and environmental stimuli trigger the unique immune cells, mast cells, which could then trigger microglia leading to abnormal synaptic pruning and dysfunctional neuronal connectivity. This process could alter the “fear threshold” in the amygdala and lead to an exaggerated “fight-or-flight” reaction. The combination of corticotropin-releasing hormone (CRH), secreted under stress, together with environmental stimuli could be major contributors to the pathogenesis of ASD. Recognizing these associations and preventing stimulation of mast cells and/or microglia could greatly benefit ASD patients. Full article

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

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15 pages, 2169 KiB

Open AccessReview

Coeliac Disease and Mast Cells

by Barbara Frossi, Marco De Carli and Antonino Calabrò

Int. J. Mol. Sci. 2019, 20(14), 3400; https://doi.org/10.3390/ijms20143400 - 11 Jul 2019

Cited by 14 | Viewed by 5122

Abstract

Over the last decades, there has been an impressive progress in our understanding of coeliac disease pathogenesis and it has become clear that the disorder is the final result of complex interactions of environmental, genetic, and immunological factors. Coeliac disease is now considered [...] Read more.

Over the last decades, there has been an impressive progress in our understanding of coeliac disease pathogenesis and it has become clear that the disorder is the final result of complex interactions of environmental, genetic, and immunological factors. Coeliac disease is now considered a prototype of T-cell-mediated disease characterized by loss of tolerance to dietary gluten and the targeted killing of enterocytes by T-cell receptor αβ intraepithelial lymphocytes. Accumulating evidence, however, indicates that the induction of a gluten-specific T helper-1 response must be preceded by the activation of the innate immune system. Mast cells are key players of the innate immune response and contribute to the pathogenesis of a multitude of diseases. Here, we review the results of studies aimed at investigating the role of mast cells in the pathogenesis of coeliac disease, showing that these cells increase in number during the progression of the disease and contribute to define a pro-inflammatory microenvironment. Full article

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

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17 pages, 281 KiB

Open AccessReview

Multidisciplinary Challenges in Mastocytosis and How to Address with Personalized Medicine Approaches

by Peter Valent, Cem Akin, Karoline V. Gleixner, Wolfgang R. Sperr, Andreas Reiter, Michel Arock and Massimo Triggiani

Int. J. Mol. Sci. 2019, 20(12), 2976; https://doi.org/10.3390/ijms20122976 - 18 Jun 2019

Cited by 65 | Viewed by 5351

Abstract

Mastocytosis is a hematopoietic neoplasm defined by abnormal expansion and focal accumulation of clonal tissue mast cells in various organ-systems. The disease exhibits a complex pathology and an equally complex clinical behavior. The classification of the World Health Organization (WHO) divides mastocytosis into [...] Read more.

Mastocytosis is a hematopoietic neoplasm defined by abnormal expansion and focal accumulation of clonal tissue mast cells in various organ-systems. The disease exhibits a complex pathology and an equally complex clinical behavior. The classification of the World Health Organization (WHO) divides mastocytosis into cutaneous forms, systemic variants, and localized mast cell tumors. In >80% of patients with systemic mastocytosis (SM), a somatic point mutation in KIT at codon 816 is found. Whereas patients with indolent forms of the disease have a normal or near-normal life expectancy, patients with advanced mast cell neoplasms, including aggressive SM and mast cell leukemia, have a poor prognosis with short survival times. In a majority of these patients, multiple somatic mutations and/or an associated hematologic neoplasm, such as a myeloid leukemia, may be detected. Independent of the category of mastocytosis and the serum tryptase level, patients may suffer from mediator-related symptoms and/or osteopathy. Depending on the presence of co-morbidities, the symptomatology in such patients may be mild, severe or even life-threatening. Most relevant co-morbidities in such patients are IgE-dependent allergies, psychiatric, psychological or mental problems, and vitamin D deficiency. The diagnosis and management of mastocytosis is an emerging challenge in clinical practice and requires vast knowledge, a multidisciplinary approach, and personalized medicine procedures. In this article, the current knowledge about mastocytosis is reviewed with special emphasis on the multidisciplinary aspects of the disease and related challenges in daily practice. Full article

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

15 pages, 1836 KiB

Open AccessReview

Mast Cells in Viral, Bacterial, and Fungal Infection Immunity

by Adrian M. Piliponsky, Manasa Acharya and Nicholas J. Shubin

Int. J. Mol. Sci. 2019, 20(12), 2851; https://doi.org/10.3390/ijms20122851 - 12 Jun 2019

Cited by 56 | Viewed by 8154

Abstract

Mast cells are granule-rich immune cells that are distributed throughout the body in areas where microorganisms typically reside, such as mucosal tissues and the skin, as well as connective tissues. It is well known that mast cells have significant roles in IgE-mediated conditions, [...] Read more.

Mast cells are granule-rich immune cells that are distributed throughout the body in areas where microorganisms typically reside, such as mucosal tissues and the skin, as well as connective tissues. It is well known that mast cells have significant roles in IgE-mediated conditions, such as anaphylaxis, but, because of their location, it is also thought that mast cells act as innate immune cells against pathogens and initiate defensive immune responses. In this review, we discuss recent studies focused on mast cell interactions with flaviviruses and Candida albicans, and mast cell function in the cecal ligation and puncture model of sepsis. We selected these studies because they are clear examples of how mast cells can either promote host resistance to infection, as previously proposed, or contribute to a dysregulated host response that can increase host morbidity and mortality. Importantly, we can distill from these studies that the contribution of mast cells to infection outcomes depends in part on the infection model, including the genetic approach used to assess the influence of mast cells on host immunity, the species in which mast cells are studied, and the differential contribution of mast cell subtypes to immunity. Accordingly, we think that this review highlights the complexity of mast cell biology in the context of innate immune responses. Full article

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

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11 pages, 1225 KiB

Open AccessReview

Role of Mast Cell-Derived Adenosine in Cancer

by Yaara Gorzalczany and Ronit Sagi-Eisenberg

Int. J. Mol. Sci. 2019, 20(10), 2603; https://doi.org/10.3390/ijms20102603 - 27 May 2019

Cited by 19 | Viewed by 3798

Abstract

Accumulating evidence has highlighted the accumulation of mast cells (MCs) in tumors. However, their impact on tumor development remained controversial. Indeed, cumulative data indicate an enigmatic role for MCs in cancer, whereby depending on the circumstances, which still need to be resolved, MCs [...] Read more.

Accumulating evidence has highlighted the accumulation of mast cells (MCs) in tumors. However, their impact on tumor development remained controversial. Indeed, cumulative data indicate an enigmatic role for MCs in cancer, whereby depending on the circumstances, which still need to be resolved, MCs function to promote or restrict tumor growth. By responding to multiple stimuli MCs release multiple inflammatory mediators, that contribute to the resolution of infection and resistance to envenomation, but also have the potency to promote or inhibit malignancy. Thus, MCs seem to possess the power to define tumor projections. Given this remarkable plasticity of MC responsiveness, there is an urgent need of understanding how MCs are activated in the tumor microenvironment (TME). We have recently reported on the direct activation of MCs upon contact with cancer cells by a mechanism involving an autocrine formation of adenosine and signaling by the A3 adenosine receptor. Here we summarized the evidence on the role of adenosine signaling in cancer, in MC mediated inflammation and in the MC-cancer crosstalk. Full article

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

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6 pages, 2428 KiB

Open AccessReview

PD-L1 Expression in Mastocytosis

by Margaret Williams, Diane S. Lidke, Karin Hartmann and Tracy I. George

Int. J. Mol. Sci. 2019, 20(9), 2362; https://doi.org/10.3390/ijms20092362 - 13 May 2019

Cited by 4 | Viewed by 3019

Abstract

Programmed death 1 (PD-1), when activated by its ligands PD-L1 and PD-L2, suppresses active immune cells in normal immune regulation to limit autoimmunity and, in tumors, as a mechanism of immune evasion. PD-L1 expression has been described as both a prognostic and predictive [...] Read more.

Programmed death 1 (PD-1), when activated by its ligands PD-L1 and PD-L2, suppresses active immune cells in normal immune regulation to limit autoimmunity and, in tumors, as a mechanism of immune evasion. PD-L1 expression has been described as both a prognostic and predictive marker in many solid and hematologic neoplasms, as targeted therapies against the PD-1/PD-L1 interaction have gained clinical importance. PD-L1 expression has been assessed in a few studies on mastocytosis. We review this literature and the need for further investigation of the tumor-immune interaction in mastocytosis. Full article

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

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12 pages, 862 KiB

Open AccessReview

MicroRNA Involvement in Allergic and Non-Allergic Mast Cell Activation

by Irit Shefler, Pazit Salamon and Yoseph A. Mekori

Int. J. Mol. Sci. 2019, 20(9), 2145; https://doi.org/10.3390/ijms20092145 - 30 Apr 2019

Cited by 15 | Viewed by 4220

Abstract

Allergic inflammation is accompanied by the coordinated expression of numerous genes and proteins that initiate, sustain, and propagate immune responses and tissue remodeling. MicroRNAs (miRNAs) are a large class of small regulatory molecules that are able to control the translation of target mRNAs [...] Read more.

Allergic inflammation is accompanied by the coordinated expression of numerous genes and proteins that initiate, sustain, and propagate immune responses and tissue remodeling. MicroRNAs (miRNAs) are a large class of small regulatory molecules that are able to control the translation of target mRNAs and consequently regulate various biological processes at the posttranscriptional level. MiRNA profiles have been identified in multiple allergic inflammatory diseases and in the tumor microenvironment. Mast cells have been found to co-localize within the above conditions. More specifically, in addition to being essential in initiating the allergic response, mast cells play a key role in both innate and adaptive immunity as well as in modulating tumor growth. This review summarizes the possible role of various miRNAs in the above-mentioned processes wherein mast cells have been found to be involved. Understanding the role of miRNAs in mast cell activation and function may serve as an important tool in developing diagnostic as well as therapeutic approaches in mast cell-dependent pathological conditions. Full article

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

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22 pages, 1142 KiB

Open AccessReview

Mast Cells, Angiogenesis and Lymphangiogenesis in Human Gastric Cancer

by Giuseppe Sammarco, Gilda Varricchi, Valentina Ferraro, Michele Ammendola, Michele De Fazio, Donato Francesco Altomare, Maria Luposella, Lorenza Maltese, Giuseppe Currò, Gianni Marone, Girolamo Ranieri and Riccardo Memeo

Int. J. Mol. Sci. 2019, 20(9), 2106; https://doi.org/10.3390/ijms20092106 - 29 Apr 2019

Cited by 136 | Viewed by 8430

Abstract

Gastric cancer is diagnosed in nearly one million new patients each year and it remains the second leading cause of cancer-related deaths worldwide. Although gastric cancer represents a heterogeneous group of diseases, chronic inflammation has been shown to play a role in tumorigenesis. [...] Read more.

Gastric cancer is diagnosed in nearly one million new patients each year and it remains the second leading cause of cancer-related deaths worldwide. Although gastric cancer represents a heterogeneous group of diseases, chronic inflammation has been shown to play a role in tumorigenesis. Cancer development is a multistep process characterized by genetic and epigenetic alterations during tumour initiation and progression. The stromal microenvironment is important in maintaining normal tissue homeostasis or promoting tumour development. A plethora of immune cells (i.e., lymphocytes, macrophages, mast cells, monocytes, myeloid-derived suppressor cells, Treg cells, dendritic cells, neutrophils, eosinophils, natural killer (NK) and natural killer T (NKT) cells) are components of gastric cancer microenvironment. Mast cell density is increased in gastric cancer and there is a correlation with angiogenesis, the number of metastatic lymph nodes and the survival of these patients. Mast cells exert a protumorigenic role in gastric cancer through the release of angiogenic (VEGF-A, CXCL8, MMP-9) and lymphangiogenic factors (VEGF-C and VEGF-F). Gastric mast cells express the programmed death ligands (PD-L1 and PD-L2) which are relevant as immune checkpoints in cancer. Several clinical undergoing trials targeting immune checkpoints could be an innovative therapeutic strategy in gastric cancer. Elucidation of the role of subsets of mast cells in different human gastric cancers will demand studies of increasing complexity beyond those assessing merely mast cell density and microlocalization. Full article

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

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13 pages, 1475 KiB

Open AccessReview

Mast Cells in Early Rheumatoid Arthritis

by Felice Rivellese, Francesca Wanda Rossi, Maria Rosaria Galdiero, Costantino Pitzalis and Amato de Paulis

Int. J. Mol. Sci. 2019, 20(8), 2040; https://doi.org/10.3390/ijms20082040 - 25 Apr 2019

Cited by 23 | Viewed by 5494

Abstract

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by inflammation of the synovial membrane, with thickening of the synovial layer, cellular hyperplasia, and infiltration of immune cells. Mast cells (MCs) are cells of the innate immunity present in healthy synovia and [...] Read more.

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by inflammation of the synovial membrane, with thickening of the synovial layer, cellular hyperplasia, and infiltration of immune cells. Mast cells (MCs) are cells of the innate immunity present in healthy synovia and part of the cellular hyperplasia characterizing RA synovitis. Although their presence in synovia has been well described, the exact functions and the correlation of MCs with disease development and progression have been debated, particularly because of contradictory data obtained in animal models and from patients with longstanding disease. Here, we present a revision of the literature on MCs in RA, including the most recent observations obtained from patients with early RA, indicating MCs as relevant markers of disease severity in early RA. Full article

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

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11 pages, 1465 KiB

Open AccessReview

Mast Cells and Angiogenesis in Human Plasma Cell Malignancies

by Domenico Ribatti, Roberto Tamma and Angelo Vacca

Int. J. Mol. Sci. 2019, 20(3), 481; https://doi.org/10.3390/ijms20030481 - 23 Jan 2019

Cited by 19 | Viewed by 4055

Abstract

Bone marrow angiogenesis plays an important role in the pathogenesis and progression of hematological malignancies. It is well known that tumor microenvironment promotes tumor angiogenesis, proliferation, invasion, and metastasis, and also mediates mechanisms of therapeutic resistance. An increased number of mast cells has [...] Read more.

Bone marrow angiogenesis plays an important role in the pathogenesis and progression of hematological malignancies. It is well known that tumor microenvironment promotes tumor angiogenesis, proliferation, invasion, and metastasis, and also mediates mechanisms of therapeutic resistance. An increased number of mast cells has been demonstrated in angiogenesis associated with hematological tumors. In this review we focused on the role of mast cells in angiogenesis in human plasma cell malignancies. In this context, mast cells might act as a new target for the adjuvant treatment of these tumors through the selective inhibition of angiogenesis, tissue remodeling and tumor-promoting molecules, permitting the secretion of cytotoxic cytokines and preventing mast cell-mediated immune suppression. Full article

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

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7 pages, 518 KiB

Open AccessOpinion

Mast Cells May Regulate The Anti-Inflammatory Activity of IL-37

by Theoharis C. Theoharides, Irene Tsilioni and Pio Conti

Int. J. Mol. Sci. 2019, 20(15), 3701; https://doi.org/10.3390/ijms20153701 - 29 Jul 2019

Cited by 31 | Viewed by 5392

Abstract

Mast cells are unique immune cells involved in allergic reactions, but also in immunity and inflammation. Interleukin 37 (IL-37) has emerged as an important regulatory cytokine with ability to inhibit immune and inflammatory processes. IL-37 is made primarily by macrophages upon activation of [...] Read more.

Mast cells are unique immune cells involved in allergic reactions, but also in immunity and inflammation. Interleukin 37 (IL-37) has emerged as an important regulatory cytokine with ability to inhibit immune and inflammatory processes. IL-37 is made primarily by macrophages upon activation of toll-like receptors (TLR) leading to generation of mature IL-37 via the action of caspase 1. In this review, we advance the premise that mast cells could regulate the anti-inflammatory activity of the IL-37 via their secretion of heparin and tryptase. Extracellular IL-37 could either dimerize in the presence of heparin and lose biological activity, or be acted upon by proteases that can generate even more biologically active IL-37 forms. Molecules that could selectively inhibit the secretion of mast cell mediators may, therefore, be used together with IL-37 as novel therapeutic agents. Full article

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

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8 pages, 299 KiB

Open AccessOpinion

Role of Leukotriene B₄ Receptor-2 in Mast Cells in Allergic Airway Inflammation

by Sun-Young Kwon and Jae-Hong Kim

Int. J. Mol. Sci. 2019, 20(12), 2897; https://doi.org/10.3390/ijms20122897 - 14 Jun 2019

Cited by 11 | Viewed by 3688

Abstract

Mast cells are effector cells in the immune system that play an important role in the allergic airway inflammation. Recently, it was reported that BLT2, a low-affinity leukotriene (LT) B₄ receptor, plays a pivotal role in the pathogenesis of allergic airway inflammation [...] Read more.

Mast cells are effector cells in the immune system that play an important role in the allergic airway inflammation. Recently, it was reported that BLT2, a low-affinity leukotriene (LT) B₄ receptor, plays a pivotal role in the pathogenesis of allergic airway inflammation through its action in mast cells. We observed that highly elevated expression levels of BLT2 are critical for the pathogenesis leading to allergic airway inflammation, and that if BLT2 expression is downregulated by siBLT2-mediated knockdown, allergic inflammation is dramatically alleviated. Furthermore, we demonstrated that BLT2 mediates the synthesis of vascular endothelial growth factor (VEGF) and Th2 cytokines, such as interleukin (IL)-13, in mast cells during allergic inflammation. Based on the critical roles of BLT2 in mast cells in allergic inflammation, anti-BLT2 strategies could contribute to the development of new therapies for allergic airway inflammation. Full article

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

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