scholarly journals Diverse exocytic pathways for mast cell mediators

2018 ◽  
Vol 46 (2) ◽  
pp. 235-247 ◽  
Author(s):  
Hao Xu ◽  
Na-Ryum Bin ◽  
Shuzo Sugita
Keyword(s):  
Allergic Rhinitis ◽  
Mast Cell ◽  
Cardiovascular Diseases ◽  
Mast Cells ◽  
Drug Targets ◽  
Environmental Changes ◽  
Biologically Active ◽  
Regulated Exocytosis ◽  
Molecular Components ◽  
Sodium Cromoglicate

Mast cells play pivotal roles in innate and adaptive immunities but are also culprits in allergy, autoimmunity, and cardiovascular diseases. Mast cells respond to environmental changes by initiating regulated exocytosis/secretion of various biologically active compounds called mediators (e.g. proteases, amines, and cytokines). Many of these mediators are stored in granules/lysosomes and rely on intricate degranulation processes for release. Mast cell stabilizers (e.g. sodium cromoglicate), which prevent such degranulation processes, have therefore been clinically employed to treat asthma and allergic rhinitis. However, it has become increasingly clear that different mast cell diseases often involve multiple mediators that rely on overlapping but distinct mechanisms for release. This review illustrates existing evidence that highlights the diverse exocytic pathways in mast cells. We also discuss strategies to delineate these pathways so as to identify unique molecular components which could serve as new drug targets for more effective and specific treatments against mast cell-related diseases.

scholarly journals Anaphylactic Degranulation of Mast Cells: Focus on Compound Exocytosis

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Ofir Klein ◽  
Ronit Sagi-Eisenberg
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Molecular Mechanisms ◽  
Secretory Granules ◽  
Cell Types ◽  
Secretory Cells ◽  
Regulated Exocytosis ◽  
Open Questions ◽  
Conflicting Evidence ◽  
Compound Exocytosis

Anaphylaxis is a notorious type 2 immune response which may result in a systemic response and lead to death. A precondition for the unfolding of the anaphylactic shock is the secretion of inflammatory mediators from mast cells in response to an allergen, mostly through activation of the cells via the IgE-dependent pathway. While mast cells are specialized secretory cells that can secrete through a variety of exocytic modes, the most predominant mode exerted by the mast cell during anaphylaxis is compound exocytosis—a specialized form of regulated exocytosis where secretory granules fuse to one another. Here, we review the modes of regulated exocytosis in the mast cell and focus on compound exocytosis. We review historical landmarks in the research of compound exocytosis in mast cells and the methods available for investigating compound exocytosis. We also review the molecular mechanisms reported to underlie compound exocytosis in mast cells and expand further with reviewing key findings from other cell types. Finally, we discuss the possible reasons for the mast cell to utilize compound exocytosis during anaphylaxis, the conflicting evidence in different mast cell models, and the open questions in the field which remain to be answered.

scholarly journals Molecular Mechanisms of Mast Cell Activation by Cholesterol-Dependent Cytolysins

2021 ◽  
Vol 12 ◽  
Author(s):  
Lubica Draberova ◽  
Magda Tumova ◽  
Petr Draber
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Signaling Pathways ◽  
Inflammatory Mediators ◽  
Pore Formation ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Biologically Active ◽  
Mast Cell Activation ◽  
Concentration Changes

Mast cells are potent immune sensors of the tissue microenvironment. Within seconds of activation, they release various preformed biologically active products and initiate the process of de novo synthesis of cytokines, chemokines, and other inflammatory mediators. This process is regulated at multiple levels. Besides the extensively studied IgE and IgG receptors, toll-like receptors, MRGPR, and other protein receptor signaling pathways, there is a critical activation pathway based on cholesterol-dependent, pore-forming cytolytic exotoxins produced by Gram-positive bacterial pathogens. This pathway is initiated by binding the exotoxins to the cholesterol-rich membrane, followed by their dimerization, multimerization, pre-pore formation, and pore formation. At low sublytic concentrations, the exotoxins induce mast cell activation, including degranulation, intracellular calcium concentration changes, and transcriptional activation, resulting in production of cytokines and other inflammatory mediators. Higher toxin concentrations lead to cell death. Similar activation events are observed when mast cells are exposed to sublytic concentrations of saponins or some other compounds interfering with the membrane integrity. We review the molecular mechanisms of mast cell activation by pore-forming bacterial exotoxins, and other compounds inducing cholesterol-dependent plasma membrane perturbations. We discuss the importance of these signaling pathways in innate and acquired immunity.

The Inferior Turbinate Mast Cell Population of Patients with Perennial Allergic and Nonallergic Rhinitis

1997 ◽  
Vol 11 (1) ◽  
pp. 63-66 ◽  
Author(s):  
Gilead Berger ◽  
Arnon Goldberg ◽  
Dov Ophir
Keyword(s):  
Allergic Rhinitis ◽  
Mast Cell ◽  
Mast Cells ◽  
Inferior Turbinate ◽  
Blue Staining ◽  
Perennial Allergic Rhinitis ◽  
Nonallergic Rhinitis ◽  
Cell Counts ◽  
Significant Difference ◽  
Normal Controls

The number of mast cells in the inferior turbinates of patients with perennial allergic rhinitis and perennial nonallergic rhinitis was compared with normal controls. Mast cell counts expressed as the mean number in 100 high-power fields, assessed after Carnoy's fixation and toluidine blue staining were 1.84 in normal controls (n = 11), 4.39 in patients with perennial allergic rhinitis (n = 13), and 4.00 in those with perennial nonallergic rhinitis (n = 26). Statistical analysis confirmed that the density of mast cells in allergic as well as in nonallergic patients was significantly higher than in normal controls, whereas no significant difference was found between the number of mast cells in allergic and nonallergic patients. It is concluded that the number of mast cells in the inferior turbinate mucosa of patients with perennial rhinitis is increased compared with normal controls, and the increased number is not necessarily allergy-dependent.

Increase of Mast Cell-Nerve Association and Neuropeptide Receptor Expression on Mast Cells in Perennial Allergic Rhinitis

2016 ◽  
Vol 23 (5-6) ◽  
pp. 261-270 ◽  
Author(s):  
Duc Dung Le ◽  
David Schmit ◽  
Sebastian Heck ◽  
Albert Joachim Omlor ◽  
Martina Sester ◽  
...  
Keyword(s):  
Allergic Rhinitis ◽  
Mast Cell ◽  
Mast Cells ◽  
Receptor Expression ◽  
Perennial Allergic Rhinitis

Anticoagulantly active heparin-like molecules from mast cell-deficient mice

1986 ◽  
Vol 250 (5) ◽  
pp. H879-H888 ◽  
Author(s):  
J. A. Marcum ◽  
J. B. McKenney ◽  
S. J. Galli ◽  
R. W. Jackman ◽  
R. D. Rosenberg
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Enzyme Inhibitor ◽  
Biologically Active ◽  
Time Interval ◽  
Heparin Binding ◽  
Similar Time ◽  
A Minor ◽  
Deficient Mice

To assess the contribution of mast cells to the maintenance of blood fluidity, the hindlimb vasculature of mast cell-deficient mice (W/Wv) and littermates containing normal levels of mast cells (+/+), were perfused with purified human thrombin and antithrombin. Enzyme-inhibitor complex generation within the vasculature was enhanced to a comparable extent for W/Wv and +/+ mice over the uncatalyzed rate, that level of complex produced within a similar time interval in the absence of heparin. Perfusion of purified Flavobacterium heparinase prior to infusion of the hemostatic components, or perfusion of antithrombin modified at the heparin-binding domain, reduced W/Wv and +/+ hindlimb thrombin-antithrombin complex formation to the uncatalyzed rate. To further define the cellular source of the vascular-associated heparin-like molecules, endothelial cells isolated from epididymal fat pads of W/Wv and +/+ mice were grown in vitro. The acceleration of thrombin-antithrombin interactions in the presence of endothelial cell-derived glycosaminoglycans was similar for W/Wv and +/+ mice, was abolished with purified bacterial heparinase, and was expressed to only a minor extent when utilizing modified antithrombin. The biologically active mucopolysaccharides appear to be present on the cell surface.

scholarly journals Rapid and specific conversion of precursor interleukin 1 beta (IL-1 beta) to an active IL-1 species by human mast cell chymase.

1991 ◽  
Vol 174 (4) ◽  
pp. 821-825 ◽  
Author(s):  
H Mizutani ◽  
N Schechter ◽  
G Lazarus ◽  
R A Black ◽  
T S Kupper
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Secretory Granules ◽  
Interleukin 1 ◽  
Critical Role ◽  
Biologically Active ◽  
Surrounding Tissue ◽  
Human Mast Cell ◽  
Interleukin 1 Beta ◽  
Mast Cell Chymase

Secretory granules of human dermal mast cells contain a chymotrypsin-like serine proteinase called chymase. In this study, we demonstrate that the inactive cytokine, 31 kD interleukin 1 beta (IL-1 beta), can be converted rapidly to an 18 kD biologically active species by human mast cell chymase. The product formed is three amino acids longer at the amino terminus than the mature IL-1 beta produced by peripheral blood mononuclear cells and has comparable biological activity. Because chymase is a secretory granule constituent, it is likely to be released into the surrounding tissue when mast cells degranulate. It is also known that non-bone marrow derived cells resident in skin (keratinocytes, fibroblasts) produce but do not process 31 kD IL-1 beta. In this context, chymase may be a potent activator of locally produced 31 kD IL-1 beta. Mast cells lie in close apposition to blood vessels in dermis; therefore, chymase mediated conversion of 31 kD IL-1 beta might be expected to have a critical role in the initiation of the inflammatory response in skin.

Mast cell ultrastructure in the inferior turbinate and stroma of nasal polyps

1997 ◽  
Vol 111 (4) ◽  
pp. 340-345 ◽  
Author(s):  
Adrian Drake-Lee ◽  
Jacqueline Price
Keyword(s):  
Allergic Rhinitis ◽  
Mast Cell ◽  
Mast Cells ◽  
Nasal Polyps ◽  
Inferior Turbinate ◽  
Cell Ultrastructure ◽  
Mast Cell Degranulation ◽  
Perennial Allergic Rhinitis ◽  
Ultrastructural Examination ◽  
Essentially Normal

AbstractFourteen unselected adult patients with nasal polyps had ultrastructural examination of mast cells from matching biopsies of the polyp and inferior turbinate. Between three and 10 blocks were examined for each patient in both tissues and every mast cell that had a nucleus was photographed for study. Fifty-three mast cells were found within the stroma of nasal polyps and 54 in the submucosa of the inferior turbinate biopsies. The number of granules ranged between 13 and 167 (mean 60) for polyps and 18 and 148 (mean 61) in the inferior turbinate. The mast cells appeared essentially normal in the inferior turbinate of four patients. The degree of degranulation of the mast cells was calculated as in previous studies and then averaged for both the polyp and the inferior turbinate of each patient. There was greater degranulation in the nasal polyp compared to inferior turbinate (p= 0.03). These results were compared with mast cell degranulation found in the normal nose and in the inferior turbinate of patients with perennial allergic rhinitis which we previously published. The inferior turbinates in these patients were more degranulated than the normal nose (p= 0.0001) but were similar to that found in patients with perennial allergic rhinitis. This suggested that some degree of degranulation may occur throughout the nose in two thirds of the patients with nasal polyps which supports the theory that mast cell reactions are not limited to the polyps in a proportion of patients.

Human mast cells release the migraine-inducing factor pituitary adenylate cyclase-activating polypeptide (PACAP)

Cephalalgia ◽  
2017 ◽  
Vol 38 (9) ◽  
pp. 1564-1574 ◽  
Author(s):  
Angela J Okragly ◽  
S Michelle Morin ◽  
David DeRosa ◽  
Andrea P Martin ◽  
Kirk W Johnson ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Adenylate Cyclase ◽  
Cell Activation ◽  
Mast Cell Degranulation ◽  
Biologically Active ◽  
Mast Cell Activation ◽  
Human Mast Cells ◽  
Pituitary Adenylate Cyclase ◽  
Ige Mediated

Background Many patients with migraines suffer from allergies and vice versa, suggesting a relationship between biological mechanisms of allergy and migraine. It was proposed many years ago that mast cells may be involved in the pathophysiology of migraines. We set out to investigate the relationship between mast cell activation and known neurogenic peptides related to migraine. Methods Cultured human mast cells were assayed for the presence of neuropeptides and their receptors at the RNA and protein level. Immunohistochemistry analyses were performed on tissue resident and cultured mast cells. Mast cell degranulation assays were performed and pituitary adenylate cyclase-activating polypeptide (PACAP) activity was measured with a bioassay. Results We found that cultured and tissue resident human mast cells contain PACAP in cytoplasmic granules. No other neurogenic peptide known to be involved in migraine was detected, nor did mast cells express the receptors for PACAP or other neurogenic peptides. Furthermore, mast cell degranulation through classic IgE-mediated allergic mechanisms led to the release of PACAP. The PACAP released from mast cells was biologically active, as demonstrated using PACAP receptor reporter cell lines. We confirmed existing literature that mast cell degranulation can also be induced by several neurogenic peptides, which also resulted in PACAP release. Conclusion Our data provides a potential biological explanation for the association between allergy and migraine by demonstrating the release of biologically active PACAP from mast cells.

scholarly journals Mast Cell, the Neglected Member of the Tumor Microenvironment: Role in Breast Cancer

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Angélica Aponte-López ◽  
Ezequiel M. Fuentes-Pananá ◽  
Daniel Cortes-Muñoz ◽  
Samira Muñoz-Cruz
Keyword(s):  
Breast Cancer ◽  
Mast Cell ◽  
Mast Cells ◽  
Cancer Progression ◽  
Elevated Serum ◽  
Protective Role ◽  
Develop Breast Cancer ◽  
Biologically Active ◽  
Angiogenic Factor ◽  
Breast Cancer Patients

Mast cells are unique tissue-resident immune cells that secrete a diverse array of biologically active compounds that can stimulate, modulate, or suppress the immune response. Although mounting evidence supports that mast cells are consistently infiltrating tumors, their role as either a driving or an opposite force for cancer progression is still controversial. Particularly, in breast cancer, their function is still under discussion. While some studies have shown a protective role, recent evidence indicates that mast cells enhance blood and lymphatic vessel formation. Interestingly, one of the most important components of the mast cell cargo, the serine protease tryptase, is a potent angiogenic factor, and elevated serum tryptase levels correlate with bad prognosis in breast cancer patients. Likewise, histamine is known to induce tumor cell proliferation and tumor growth. In agreement, mast cell depletion reduces the size of mammary tumors and metastasis in murine models that spontaneously develop breast cancer. In this review, we will discuss the evidence supporting protumoral and antitumoral roles of mast cells, emphasizing recent findings placing mast cells as important drivers of tumor progression, as well as the potential use of these cells or their mediators as therapeutic targets.

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