scholarly journals Novel Strategies to Target Mast Cells in Disease

2021 ◽  
pp. 1-17
Author(s):  
Aida Paivandy ◽  
Gunnar Pejler
Keyword(s):  
Mast Cell ◽  
Immune System ◽  
Mast Cells ◽  
Cell Growth ◽  
Secretory Granules ◽  
Effector Cells ◽  
Host Protection ◽  
Pathological Conditions ◽  
Allergic Disorders ◽  
Detrimental Impact

Mast cells (MCs) are versatile effector cells of the immune system, characterized by a large content of secretory granules containing a variety of inflammatory mediators. They are implicated in the host protection toward various external insults, but are mostly well known for their detrimental impact on a variety of pathological conditions, including allergic disorders such as asthma and a range of additional disease settings. Based on this, there is currently a large demand for therapeutic regimens that can dampen the detrimental impact of MCs in these respective pathological conditions. This can be accomplished by several strategies, including targeting of individual mediators released by MCs, blockade of receptors for MC-released compounds, inhibition of MC activation, limiting mast cell growth or by inducing mast cell apoptosis. Here, we review the currently available and emerging regimens to interfere with harmful mast cell activities in asthma and other pathological settings and discuss the advantages and limitations of such strategies.

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.

The lysosomal protease cathepsin D is efficiently sorted to and secreted from regulated secretory compartments in the rat basophilic/mast cell line RBL

2000 ◽  
Vol 113 (18) ◽  
pp. 3289-3298 ◽  
Author(s):  
A. Dragonetti ◽  
M. Baldassarre ◽  
R. Castino ◽  
M. Demoz ◽  
A. Luini ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Cell Line ◽  
Cathepsin D ◽  
Secretory Granules ◽  
Bioactive Molecules ◽  
Blue Staining ◽  
Lysosomal Protease ◽  
Mannose 6 Phosphate ◽  
Mast Cell Line

Basophils and mast cells contain a peculiar class of inflammatory granules that discharge their content upon antigen-mediated crosslinking of IgE-membrane receptors. The pathways for granule biogenesis and exocytosis in these cells are still largely obscure. In this study we employed the rat basophilic leukemia (RBL)/mast cell line to verify the hypothesis that inflammatory granules share common bioactive molecules and functional properties with lysosomes. We demonstrate that inflammatory granules, as identified by the monoclonal 5G10 antibody (which recognises an integral membrane protein) or by Toluidine Blue staining, have an intralumenal acidic pH, possess lysosomal enzymes and are accessible by fluid-phase and membrane endocytosis markers. In addition, we studied the targeting, subcellular localisation and regulated secretion of the lysosomal aspartic protease cathepsin D (CD) as affected by IgE receptor stimulation in order to obtain information on the pathways for granule biogenesis and exocytosis. Stimulation with DNP-BSA of specific IgE-primed RBL cells led to a prompt release of processed forms of CD, along with other mature lysosomal hydrolases. This release could be prevented by addition of EGTA, indicating that it was dependent on extracellular calcium influx. Antigen stimulation also induced exocytosis of immature CD forms accumulated by ammonium chloride, suggesting the existence of an intermediate station in the pathway for granule biogenesis still sensitive to regulated exocytosis. The targeting of molecules to secretory granules may occur via either a mannose-6-phosphate-dependent or mannose-6-phosphate-independent pathway. We conclude that endosomes and lysosomes in basophils/mast cells can act as regulated secretory granules or actually identify with them.

scholarly journals The Mast Cell-Aryl Hydrocarbon Receptor Interplay at the Host-Microbe Interface

2018 ◽  
Vol 2018 ◽  
pp. 1-6
Author(s):  
Claudio Costantini ◽  
Giorgia Renga ◽  
Vasilis Oikonomou ◽  
Giuseppe Paolicelli ◽  
Monica Borghi ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Aryl Hydrocarbon Receptor ◽  
Current Knowledge ◽  
Cell Physiology ◽  
Effector Functions ◽  
Host Protection ◽  
Aryl Hydrocarbon ◽  
Environmental Agents ◽  
Sense And Respond

Mast cells are increasingly being recognized as crucial cells in the response of the organism to environmental agents. Interestingly, the ability of mast cells to sense and respond to external cues is modulated by the microenvironment that surrounds mast cells and influences their differentiation. The scenario that is emerging unveils a delicate equilibrium that balances the effector functions of mast cells to guarantee host protection without compromising tissue homeostasis. Among the environmental components able to mold mast cells and fine-tune their effector functions, the microorganisms that colonize the human body, collectively known as microbiome, certainly play a key role. Indeed, microorganisms can regulate not only the survival, recruitment, and maturation of mast cells but also their activity by setting the threshold required for the exploitation of their different effector functions. Herein, we summarize the current knowledge about the mechanisms underlying the ability of the microorganisms to regulate mast cell physiology and discuss potential deviations that result in pathological consequences. We will discuss the pivotal role of the aryl hydrocarbon receptor in sensing the environment and shaping mast cell adaptation at the host-microbe interface.

scholarly journals The emerging role of mast cell proteases in asthma

2019 ◽  
Vol 54 (4) ◽  
pp. 1900685 ◽  
Author(s):  
Gunnar Pejler
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Current Knowledge ◽  
Secretory Granules ◽  
Cross Linking ◽  
Lysosomal Hydrolases ◽  
Ige Receptor ◽  
Deficient Mice ◽  
Lines Of Evidence

It is now well established that mast cells (MCs) play a crucial role in asthma. This is supported by multiple lines of evidence, including both clinical studies and studies on MC-deficient mice. However, there is still only limited knowledge of the exact effector mechanism(s) by which MCs influence asthma pathology. MCs contain large amounts of secretory granules, which are filled with a variety of bioactive compounds including histamine, cytokines, lysosomal hydrolases, serglycin proteoglycans and a number of MC-restricted proteases. When MCs are activated, e.g. in response to IgE receptor cross-linking, the contents of their granules are released to the exterior and can cause a massive inflammatory reaction. The MC-restricted proteases include tryptases, chymases and carboxypeptidase A3, and these are expressed and stored at remarkably high levels. There is now emerging evidence supporting a prominent role of these enzymes in the pathology of asthma. Interestingly, however, the role of the MC-restricted proteases is multifaceted, encompassing both protective and detrimental activities. Here, the current knowledge of how the MC-restricted proteases impact on asthma is reviewed.

Eotaxin Modulates Myelopoiesis and Mast Cell Development From Embryonic Hematopoietic Progenitors

Blood ◽  
1998 ◽  
Vol 92 (6) ◽  
pp. 1887-1897 ◽  
Author(s):  
Elizabeth J. Quackenbush ◽  
Barry K. Wershil ◽  
Vincent Aguirre ◽  
Jose-Carlos Gutierrez-Ramos
Keyword(s):  
Mast Cell ◽  
Stem Cell ◽  
Mast Cells ◽  
Stem Cell Factor ◽  
Fetal Liver ◽  
Hematopoietic Progenitors ◽  
Embryonic Tissues ◽  
Pathological Conditions ◽  
Gi Protein ◽  
American Society

Abstract Eotaxin is a potent chemoattractant for eosinophils during inflammation and allergic reactions in the adult, but its role in the embryonic development of the hematopoietic system has not been examined. We report here that eotaxin and its receptor, CCR-3, are expressed by embryonic tissues responsible for blood development, such as fetal liver (FL), yolk sac (YS), and peripheral blood. We found that eotaxin acts synergistically with stem cell factor to accelerate the differentiation of embryonic mast cell progenitors, and this response can be suppressed by pertussis toxin, an inhibitor of chemokine-induced signaling through Gi protein and chemotaxis. Eotaxin promotes the differentiation of fetal mast cell progenitors into differentiated mast cells as defined by the expression of mast cell specific proteases. Furthermore, in combination with stem cell factor (SCF), it promotes the growth of Mac-1+myeloid cells from embryonic progenitors. These studies suggest that eotaxin may be involved in the growth of granulocytic progenitors and the differentiation and/or function of mast cells during embryogenesis and/or pathological conditions that induce high levels of eotaxin, such as allergic responses. © 1998 by The American Society of Hematology.

scholarly journals Glutamate triggers the expression of functional ionotropic and metabotropic glutamate receptors in mast cells

2020 ◽  
Author(s):  
Md Abdul Alim ◽  
Mirjana Grujic ◽  
Paul W. Ackerman ◽  
Per Kristiansson ◽  
Pernilla Eliasson ◽  
...  
Keyword(s):  
Mast Cell ◽  
Immune System ◽  
Mast Cells ◽  
Glutamate Receptors ◽  
Glutamate Receptor ◽  
Metabotropic Glutamate Receptors ◽  
Cell Function ◽  
Metabotropic Glutamate ◽  
Protein Levels

Abstract Mast cells are emerging as players in the communication between peripheral nerve endings and cells of the immune system. However, it is not clear the mechanism by which mast cells communicate with peripheral nerves. We previously found that mast cells located within healing tendons can express glutamate receptors, raising the possibility that mast cells may be sensitive to glutamate signaling. To evaluate this hypothesis, we stimulated primary mast cells with glutamate and showed that glutamate induced the profound upregulation of a panel of glutamate receptors of both the ionotropic type (NMDAR1, NMDAR2A, and NMDAR2B) and the metabotropic type (mGluR2 and mGluR7) at both the mRNA and protein levels. The binding of glutamate to glutamate receptors on the mast cell surface was confirmed. Further, glutamate had extensive effects on gene expression in the mast cells, including the upregulation of pro-inflammatory components such as IL-6 and CCL2. Glutamate also induced the upregulation of transcription factors, including Egr2, Egr3 and, in particular, FosB. The extensive induction of FosB was confirmed by immunofluorescence assessment. Glutamate receptor antagonists abrogated the responses of the mast cells to glutamate, supporting the supposition of a functional glutamate–glutamate receptor axis in mast cells. Finally, we provide in vivo evidence supporting a functional glutamate–glutamate receptor axis in the mast cells of injured tendons. Together, these findings establish glutamate as an effector of mast cell function, thereby introducing a novel principle for how cells in the immune system can communicate with nerve cells.

Recognition Sites for Microbes and Components of the Immune System on Human Mast Cells: Relationship to CD Antigens and Implications for Host Defense

2007 ◽  
Vol 20 (3) ◽  
pp. 421-434 ◽  
Author(s):  
M. Mayerhofer ◽  
K.J. Aichberger ◽  
S. Florian ◽  
P. Valent
Keyword(s):  
Immune System ◽  
Mast Cells ◽  
Host Defense ◽  
Specific Ige ◽  
Specific Cell ◽  
Surface Binding ◽  
Helminth Infections ◽  
Life Threatening ◽  
Current Article ◽  
Allergic Disorders

Traditionally, mast cells (MCs) have been considered to play an important role in allergic disorders and helminth infections. More recently, MCs have been implicated in a variety of different infectious diseases including life-threatening disorders caused by viruses and bacteria. Apart from recognition through specific IgE, MCs are considered to recognize such bacteria and viruses via specific cell surface binding sites. In addition, MCs interact with diverse components and cells of the immune system and thereby may facilitate the targeting and the elimination of invading microbes in the tissues. The current article provides an overview on MC antigens contributing to microbe recognition and targeting as an important element of natural host-defense.

scholarly journals Angiogenic factors stimulate mast-cell migration

Blood ◽  
1995 ◽  
Vol 86 (7) ◽  
pp. 2488-2493 ◽  
Author(s):  
BL Gruber ◽  
MJ Marchese ◽  
R Kew
Keyword(s):  
Mast Cell ◽  
Endothelial Cell ◽  
Growth Factor ◽  
Mast Cells ◽  
Cell Growth ◽  
Chemotactic Factor ◽  
Angiogenic Factor ◽  
Directed Migration ◽  
Endothelial Cell Growth Factor ◽  
Endothelial Cell Growth

Abstract Mast cells accumulate at sites of angiogenesis. The factor(s) that control mast-cell recruitment at these sites have yet to be defined. We sought to determine if angiogenic factors result in mast-cell chemotaxis. In this study, we observed that platelet-derived growth factor-AB (PDGF-AB), vascular endothelial cell growth factor (VEGF), and basic fibroblast growth factor (bFGF) each cause directed migration of murine mast cells at picomolar concentrations, with a typical bell-shaped dose-response curve. Another potent angiogenic factor, platelet-derived endothelial cell growth factor (PD-ECGF), appears to promote chemokinesis of mast cells, whereas tumor necrosis factor-alpha, a weak angiogenic factor, is less robust but still functions as a mast cell chemotactic factor. Epidermal growth factor (EGF), a growth factor with minimal angiogenic properties, was ineffective as a mast cell chemotactic factor. A checkerboard analysis confirmed the directional chemotactic response of PDGF-AB, VEGF, and bFGF, while indicating the chemokinetic response induced by PD-ECGF. Cross-desensitization of growth-factor-induced directed migration was observed between PDGF-AB and bFGF, and also between PDGF-AB and PD-ECGF. Tyrosine kinase-inhibitor genistein effectively dampened the chemotactic responses, whereas pertussis toxin had no effect. In summary, our findings suggest that factors known to act on endothelial cells and stimulate neovascularization may simultaneously serve to recruit mast cells to these sites. The local accumulation of mast cells is believed to facilitate new vessel formation through complex cell:cell interactions.

Mast cells are crucial for early inflammation, migration of Langerhans cells, and CTL responses following topical application of TLR7 ligand in mice

Blood ◽  
2007 ◽  
Vol 110 (3) ◽  
pp. 946-953 ◽  
Author(s):  
Valeska Heib ◽  
Marc Becker ◽  
Tobias Warger ◽  
Gerd Rechtsteiner ◽  
Christine Tertilt ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Topical Application ◽  
Langerhans Cells ◽  
Cytotoxic T Lymphocyte ◽  
Effector Cells ◽  
Tnf Α ◽  
Transcutaneous Immunization ◽  
Antigen Presenting ◽  
Tlr7 Ligand

Abstract Until recently, IgE-activated mast cells have been regarded merely as effector cells of adaptive immune responses, involved in allergic reactions and mucosal immunity to parasites. Herein, we report that murine dermal mast cells, activated by local administration of a cream containing the synthetic TLR7 ligand imiquimod, are essential to initiate an early inflammatory reaction. The mast-cell–derived cytokines TNF-α and IL-1β play an important role in this process. Furthermore, TLR7-activated mast cells are also able to promote the emigration of Langerhans cells, which partly depends on the expression of mast-cell–derived IL-1β. We have previously shown that TLR7 ligation enhances transcutaneous immunization evoked by topical application of vaccine antigens to the skin, a procedure that directly targets skin-resident antigen-presenting cells. Consequently, we now demonstrate here that the capacity to mount a peptide-specific cytotoxic T-lymphocyte response following transcutaneous immunization using imiquimod as adjuvant is severely impaired in mast-cell–deficient mice. Thus, these findings demonstrate the potent versability of alternatively activated mast cells at the interface of innate and adaptive immunity.

scholarly journals Effects of early life adversity on meningeal mast cells and proinflammatory gene expression in male and female Mus musculus

2021 ◽  
Author(s):  
Natalia Duque-Wilckens ◽  
Erika Sarno ◽  
Robby E. Teis ◽  
Frauke Stoelting ◽  
Sonia Khalid ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mast Cell ◽  
Immune System ◽  
Mast Cells ◽  
Early Life ◽  
Inflammatory Markers ◽  
Disease Susceptibility ◽  
Early Life Adversity ◽  
Male And Female ◽  
The Brain

ABSTRACTExposure to early life adversity (ELA) in the form of physical and/or psychological abuse or neglect increases the risk of developing psychiatric and inflammatory disorders later in life. It has been hypothesized that exposure to ELA results in persistent, low grade inflammation that leads to increased disease susceptibility by amplifying the crosstalk between stress-processing brain networks and the immune system, but the mechanisms remain largely unexplored. The meninges, a layer of three overlapping membranes that surround the central nervous system (CNS)- duramater, arachnoid, and piamater – possess unique features that allow them to play a key role in coordinating immune trafficking between the brain and the peripheral immune system. These include a network of lymphatic vessels that carry cerebrospinal fluid from the brain to the deep cervical lymph nodes, fenestrated blood vessels that allow the passage of molecules from blood to the CNS, and a rich population of resident mast cells, master regulators of the immune system. Using a mouse model of ELA consisting of neonatal maternal separation plus early weaning (NMSEW), we sought to explore the effects of ELA on duramater mast cell histology and expression of inflammatory markers in male and female C57Bl/6 mice. We found that mast cell number, activation level, and relative expression of pseudopodia differ across duramater regions, and that NMSEW exerts region-specific effects on mast cells in males and females. Using gene expression analyses, we next found that NMSEW increases the expression of inflammatory markers in the duramater of females but not males, and that this is prevented by pharmacological inhibition of mast cells with ketotifen. Together, our results show that ELA drives sex-specific, long-lasting effects on the duramater mast cell population and immune-related gene expression, suggesting that the long-lasting effects of ELA on disease susceptibility could be partly mediated by meningeal function.

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