Mast-cell responses in the development of asthma

doi:10.1016/S0091-6749(00)90056-3

Journal of Allergy and Clinical Immunology

Volume 105, Issue 2, Part 2, February 2000, Pages S527-S534

https://doi.org/10.1016/S0091-6749(00)90056-3 Get rights and content

Abstract

Many cells participate in the pathogenesis of asthmatic inflammation. The mast cell is localized at the interface of the internal and external environment within the lung where it may respond to allergens and other exogenous stimuli. The activation of mast cells leads to the release of mediators that contribute to the early phase of asthmatic inflammation. Mast-cell–derived products may also contribute to the late-phase asthmatic response. This review summarizes the developmental biologic features of the mast cell, its receptor-mediated activation, and its range of preformed, newly synthesized, and induced mediators that contribute to asthmatic inflammation. (J Allergy Clin Immunol 2000;105:S527-34.)

Section snippets

DEVELOPMENT OF MAST CELLS

The human mast cell is derived from a CD34⁺ bone marrow progenitor.¹ Circulating progenitor mast cells are recognized by the surface expression of the receptor tyrosine kinase c-kit (CD 117), the receptor for stem-cell factor (SCF), a marker lost during the development of other hematopoietic cells including basophils.² Circulating progenitor mast cells express the receptor that binds IgG with low affinity, FcγRIIb, before the expression of the high-affinity receptor for IgE (FcϵRI), and contain

MAST-CELL ACTIVATION

Classic mast-cell activation occurs through FcϵRI, a tetrameric complex of an extracellular α chain that binds the Fc portion of IgE, a transmembrane β chain, and 2 disulfide-linked transmembrane γ chains that participate in signal transduction.²⁷ When adjacent receptors are crosslinked by multivalent antigen or by haptens, the phosphorylation of the β and γ chains within the immunoregulatory tyrosine–activation motifs (ITAMs), common to other transmembrane receptors, recruits and activates the

PREFORMED MAST-CELL MEDIATORS

The metachromatic staining of the human mast-cell secretory granule is due to the heavily sulfated anionic proteoglycans, heparin and chondroitin sulfate glycosaminoglycan, linked to a novel peptide core, serglycin. These proteoglycans stabilize proteases in the granule.60, 61 Heparin acts as an anticoagulant, inhibits the complement cascade, potentiates angiogenic factors such as basic fibroblast growth factor, and binds low- molecular–weight PLA₂ enzymes. Chondroitin sulfate also activates

NEWLY FORMED EICOSANOID MEDIATORS

The mast cell generates substantial amounts of both the cysteinyl leukotriene C₄ and the prostanoid PGD₂. The constitutive pathways for generation of these products include group IV cPLA₂, 5-lipoxygenase, 5-1ipoxygenase–activating protein, and leukotriene C₄ synthase for leukotriene C₄; cPLA₂ in addition to at least 1 species of low-molecular–weight PLA₂, prostaglandin endoperoxide synthase-1 (or cyclooxygenase-1), and hematopoietic PGD₂ synthase for PGD₂.⁷⁷ In addition to eicosanoids, mast

CYTOKINES

The mast cell generates a range of multifunctional cytokines that may participate in the development of asthma.⁹⁴ Mast cells with different protease phenotypes display heterogeneity in their cytokine profiles.⁹⁵ The generation of the T_H2 cytokines (IL-4, IL-5, IL-13, GM-CSF) has been well described in both in vivo and in vitro studies of human mast cells.96, 97, 98 IL-4 and IL-13 generated by mast cells may further amplify the production of IgE by B cells and promote the upregulation of T_H2

SUMMARY (Fig 1)

. Mast-cell interactions in asthmatic inflammation. Mast-cell–derived products may interact with target cells in the microenvironment of the lung in the initiation and perpetuation of asthma. Products derived from other cells may also regulate mast-cell function. FGF , Basic fibroblast growth factor; LT , leukotriene.

Because of its localization in the airway at an interface between the internal and external environment, the mast cell is positioned to respond to exogenous airborne antigens against

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Th2-high asthma is characterized by elevated blood and airway levels of eosinophils; CD4+ T-helper (Th)-2 cells; and the cytokines interleukin (IL) 4, 5, and 13.5 Th2 cells and group 2 innate lymphoid cells (ILC2s) express CRTh2 (chemoattractant receptor–homologous molecule expressed on Th2 cells),6,7 a receptor of the lipid mediator prostaglandin (PG)D2,8 which is released from mast cells following allergen–immunoglobulin (Ig) E crosslinking9 as well as other cells.10 PGD2 activation of CRTh2 leads to Th2-mediated cytokine production,11 chemotaxis,8,12 and inhibition of apoptosis,13 all effects that may exacerbate Th2-mediated inflammation.
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Patients with stress-triggered asthma (n = 12) had higher percentage of CD4⁺ T cells (P = 0.006) and Th2 cells (CD4⁺CRTh2⁺ T cells; P = 0.002) in peripheral blood compared to patients with asthma who did not experience stress-related worsening of disease (n = 54). The same was true when we analyzed patients with any form of psychological comorbidity (n = 19) compared to those without psychological comorbidities (n = 47). These differences were evident among women, but not among men. Women with psychological comorbidity also required higher doses of inhaled and oral corticosteroids compared to those without psychological comorbidity.
Asthma involving psychological morbidity associates with an elevated level of circulating Th2 cells and increased corticosteroid usage, and may be more prevalent in women. Larger-scale prospective studies are required for assessing whether these women constitute a new endotype of Th2-high asthma responsive to treatments aimed to improve psychological comorbidities.
Kinase inhibitors in the treatment of obstructive pulmonary diseases
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Mast cells, T-cells, eosinophils, and neutrophils all play key roles in the inflammatory response seen in obstructive pulmonary diseases [2]. Mast cell activation involves the RTK c-Kit, non-receptor tyrosine kinases, such as Lyn and Syk, PKC, and ERK MAP kinase signaling [52]. PI3K isoforms play a prominent role in the differentiation, proliferation, survival, and cytokine production of immune cells [53] and pharmacological inhibition of PI3K suppresses T-helper cell cytokine production and eosinophil infiltration in mice challenged with ovalbumin [54].
Chronic pulmonary diseases, including chronic obstructive pulmonary disease (COPD) and asthma, are major causes of death and reduced quality of life. Characteristic of chronic pulmonary disease is excessive lung inflammation that occurs in response to exposure to inhaled irritants, chemicals, and allergens. Chronic inflammation leads to remodeling of the airways that includes excess mucus secretion, proliferation of smooth muscle cells, increased deposition of extracellular matrix proteins and fibrosis. Protein kinases have been implicated in mediating inflammatory signals and airway remodeling associated with reduced lung function in chronic pulmonary disease. This review will highlight the role of protein kinases in the lung during chronic inflammation and examine opportunities to use protein kinase inhibitors for the treatment of chronic pulmonary diseases.
Histamine H <inf>4</inf> receptor mediates chemotaxis of human lung mast cells
2018, European Journal of Pharmacology
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Following activation by allergens, the mast cell can release histamine as well as generate a host of additional mediators such as cysteinyl-leukotrienes (cys-LTs) and prostaglandin D2 (PGD2). These mediators act in concert to promote inflammation and, if mast cell activation occurs in the lung, these mediators can promote potent bronchoconstriction (Bingham and Austen, 2000; Bradding et al., 2006). There have been a few studies investigating the effects of histamine on mast cells but the majority of these has been on rodent and cultured mast cells (Hofstra et al., 2003; Lippert et al., 2004; Jemima et al., 2014).
The diverse effects of histamine are mediated by discrete histamine receptors. The principal repository of histamine in the body is the mast cell. However, the effects of histamine on mast cells, especially those of human origin, have not been fully elucidated. In this study, the expression of histamine receptors in human lung mast cells was evaluated. Moreover, the effects of histamine receptor engagement on both mediator release and chemotaxis were investigated. Mast cells were isolated and purified from human lung tissue. Histamine receptor expression was determined by RT-PCR and q-PCR. Both methods for the detection of histamine receptors were in accordance and human lung mast cells expressed mRNA for histamine H₄ and histamine H₁ receptors, variably expressed histamine H₂ receptor but did not express histamine H₃ receptor. The effects of selective histamine receptor agonists on the release of both pre-formed (histamine) and newly-synthesised (cysteinyl-leukotriene, prostaglandin D₂) mediators were investigated. None of the agonists tested had any direct effects on mediator release. None of the agonists modulated release stimulated by anti-IgE. Further studies showed that histamine induced migration of mast cells. Chemotaxis appeared to be mediated by the histamine H₄ receptor since JNJ28610244 (H₄ agonist) was chemotactic for mast cells whereas 2-(2-pyridyl) ethylamine (H₁ agonist) was not. Furthermore, the selective histamine H₄ receptor antagonist, JNJ7777120, effectively reversed the chemotaxis of mast cells induced by JNJ28610244. Overall, these experiments identify the histamine H₄ receptor as chemotactic for human lung mast cells. This mechanism might influence mast cell accumulation in the lung.
Prostaglandin D<inf>2</inf> generation from human lung mast cells is catalysed exclusively by cyclooxygenase-1
2018, European Journal of Pharmacology
Mast cells are an exceptionally rich source of prostaglandin D₂ (PGD₂). PGD₂ is pro-inflammatory and can cause bronchoconstriction. The enzyme cyclooxygenase (COX) is central to the generation of prostanoids such as PGD₂. Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit COX. COX exists as two isoforms, COX-1 and COX-2. The principal aim of this study was to establish whether COX-1 and/or COX-2 mediates PGD₂ generation from human lung mast cells. Mast cells were isolated from human lung tissue and purified by flotation over Percoll and immunomagnetic bead separations. The cells were activated with anti-IgE or Stem Cell Factor (SCF). The generation of PGD₂ was determined by ELISA. The effects of NSAIDs (aspirin, ibuprofen, diclofenac, naproxen, indomethacin), COX-1 selective (FR122047), and COX-2 selective (celecoxib) inhibitors on PGD₂ generation were determined. The expression of COX-1 and COX-2 in mast cells was determined by Western blotting. All the NSAIDs tested abrogated stimulated PGD₂ generation from mast cells except aspirin which was only weakly effective. FR122047 was an effective inhibitor of PGD₂ generation (EC₅₀ ~25 nM) from mast cells whereas celecoxib was ineffective. Immunoblotting indicated that COX-1 was strongly expressed in all mast cell preparations while COX-2 expression was weak. No induction of COX-2 was observed following activation of mast cells. These findings indicate that COX-1 is the principal isoform involved in generating PGD₂ from human lung mast cells. These studies provide insight into the potential behaviour of NSAIDs in the context of respiratory diseases.
Toll-like receptor-mediated involvement of innate immune cells in asthma disease
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Also, limited data are available regarding the detection of TLRs protein in the lungs [35]. Mast cells (MC) strategically reside near the surface of the airway epithelium and the deeper layers of the mucosa [49]. During the development of the sensitization process, they are accumulated in both sub-mucosa and smooth muscles of the airways [49].
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This review discusses how recruitment and accumulation of the inflammatory cells in the site of insult facilitate hypersensitivity reactions and initiate airway inflammation. We indicate that these cells are well equipped to highly sensitive receptors known as toll-like receptors (TLRs) making them fit to prime adaptive immune response. Based on emerging findings, we highlight the pivotal role of TLRs in regulation of innate cells function in the context of asthma disease.
Stimulation of the TLRs of innate cells by allergens has been found to accelerate and regulate allergic airway inflammation. In fact, the sophisticated interaction between environmental allergens and TLRs leads to release of various pro-inflammatory mediators from innate cells supporting asthma development.
This review highlights that TLRs have a substantial role in priming innate cells and cytokine release, suggesting that the involvement of TLRs of innate immune cells can modulate the function of these cells in asthma disease.
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2008, Asthma and COPD: Basic Mechanisms and Clinical Management
This chapter summarizes current thinking about roles of mast cells and basophils in obstructive airway disease. Mast cells and basophils first came to attention over a century ago due to their ample stocks of intracellular granules with unusual staining characteristics. Mast cells, but not basophils, are normal residents of uninflamed airways. Mature mast cells rarely appear in blood, whereas mature basophils circulate and are recruited from blood to sites of allergic inflammation. Mast cells protect from certain types of infection and injury by contributing to innate and adaptive immune responses. The homeostatic roles of basophils are less clear. Both cell types participate in the pathology of atopy and asthma by deploying an arsenal of inflammatory mediators. Several experiments in mice support a role for mast cells in asthma-like allergic inflammation, including eosinophilia, hyperresponsiveness, and epithelial remodeling. Notwithstanding some studies questioning its importance in mice, IgE's long-suspected contributions to human asthma are supported by trials by using anti-IgE antibodies, which reduce circulating IgE to nearly undetectable levels and decrease symptoms and corticosteroid use in moderate, steroid-dependent asthmatics, and rhinitics. Others, effective in animal models, include tryptase inhibitors. Support is mounting for the hypothesis that both types of cells magnify the pathology of persistent inflammation in chronic asthma, including stimulation of IgE production, recruitment of eosinophils, and remodeling of epithelium.

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^☆: Reprint requests: Clifton O. Bingham, III, MD, Department of Rheumatology and Medicine, Hospital for Joint Diseases, 301 E. 17th St., New York, NY 10003.

^☆☆: 0091-6749/2000 $12.00 + 0 1/0/99522

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Mast-cell responses in the development of asthma☆,☆☆

Abstract

Section snippets

DEVELOPMENT OF MAST CELLS

MAST-CELL ACTIVATION

PREFORMED MAST-CELL MEDIATORS

NEWLY FORMED EICOSANOID MEDIATORS

CYTOKINES

SUMMARY (Fig 1)

Adv Immunol

Blood

Blood

Immunol Today

Immunol Today

Blood

Blood

Immunity

Curr Opin Immunol

J Biol Chem

J Biol Chem

J Biol Chem

Trends Biochem Sci

J Biol Chem

J Biol Chem

J Biol Chem

J Invest Dermatol

J Biol Chem

J Invest Dermatol

Immunol Today

J Biol Chem

J Allergy Clin Immunol

Med Clin North Am

J Allergy Clin Immunol

J Biol Chem

Immunol Today

J Allergy Clin Immunol

Demonstration of the origin of human mast cells from CD34+ bone marrow progenitor cells

J Immunol

Induction of the high affinity IgE receptor (FcεRI) on human mast cells by IL-4

Int Immunol

IgE enhances mast cell FcεRI expression in vitro and in vivo: evidence for a novel amplification mechanism in IgE-dependent reactions

J Exp Med

Selective growth of human mast cells induced by steel factor, IL-6, and PGE2 from cord blood mononuclear cells

J Immunol

Evidence for morphologic diversity of human mast cells: an ultrastructural study of mast cells from multiple body sites

Lab Invest

Two types of human mast cells that have distinct neutral protease compositions

Proc Nat Acad Sci USA

Ultrastructural and immunohistochemical detection of normal mast cells at multiple body sites

J Invest Dermatol

Deficiency of tryptase-positive, chymase-negative mast cell type in gastrointestinal mucosa of patients with defective T lymphocyte function

J Immunol

Development of mast cells and basophils: role of c-kit receptor tyrosine kinase for development, survival, and neoplastic transformation of mast cells

The c-kit receptor, stem cell factor, and mast cells, what each is teaching us about the others

Am J Pathol

The kit ligand, stem cell factor

Adv Immunol

Identification of mutations in the coding region of the proto-oncogene c-kit in a human mast cell leukemia cell line causing ligand-independent activation of c-kit product

J Clin Invest

Somatic c-kit activating mutation in urticaria pigmentosa and aggressive systemic mastocytosis: establishment of a clonality in a human mast cell neoplasm

Nat Genet

Identification of a point mutation in the catalytic domain of the protooncogene c-kit in peripheral blood mononuclear cells of patients who have mastocytosis with an associated hematologic disorder

Proc Nat Acad Sci USA

Oncogenic mutation in the kit receptor tyrosine kinase alters substrate specificity and induces degradation of the protein tyrosine phosphatase SHP-1

Proc Nat Acad Sci USA

Identification of a committed precursor for the mast cell lineage

Science

Mast cells that reside at different locations in the jejunum of mice infected with Trichinella spiralis exhibit sequential changes in their granule ultrastructure and chymase phenotype

J Cell Biol

Chronically kit-stimulated clonally derived human mast cells show heterogeneity in different tissue microenvironments

J Invest Dermatol

Antigen and Fc receptor signaling: the awesome power of the immunoreceptor tyrosine based activation motif (ITAM)

J Immunol

Association of protein tyrosine kinase with phospholipase C-γ1 in bone marrow-derived mouse mast cells

Proc Nat Acad Sci USA

The complex of FK506-binding protein 12 and FK506 inhibits calcineurin phosphatase activity and IgE activation-induced cytokine transcripts but not exocytosis in mouse mast cells

J Immunol

Calcium ionophore-induced secretion from mast cells correlates with myosin light chain phosphorylation by protein kinase C

J Immunol

Protein kinases C-beta and C-epsilon link the mast cell high affinity receptor for IgE to the expression of c-fos and c-jun

Demonstration of the origin of human mast cells from CD34⁺ bone marrow progenitor cells

Selective growth of human mast cells induced by steel factor, IL-6, and PGE₂ from cord blood mononuclear cells