CC Chemokine Receptor 3 Mobilizes to the Surface of Human Mast Cells and Potentiates Immunoglobulin E–Dependent Generation of Interleukin 13

Price, Kursteen S.; Friend, Daniel S.; Mellor, Elizabeth A.; Jesus, Nidia De; Watts, Gerald F.; Boyce, Joshua A.

doi:10.1165/rcmb.2002-0155oc

Cited by 52 publications

(37 citation statements)

References 33 publications

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“…However, severe asthma epithelial cells, through enhanced expression of TGF-b, in association with Th2 cytokines and IL-9, could promote development of this MC TC phenotype (38). Similarly, Th2-induced epithelial eotaxins could also lead to MC recruitment and activation (39,40).…”

Section: Discussionmentioning

confidence: 99%

Mast Cell Phenotype, Location, and Activation in Severe Asthma

Balzar¹,

Fajt²,

Comhair³

et al. 2011

Am J Respir Crit Care Med

269

247

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Rationale: Severe asthma (SA) remains poorly understood. Mast cells (MC) are implicated in asthma pathogenesis, but it remains unknown how their phenotype, location, and activation relate to asthma severity. Objectives: To compare MC-related markers measured in bronchoscopically obtained samples with clinically relevant parameters between normal subjects and subjects with asthma to clarify their pathobiologic importance. Methods: Endobronchial biopsies, epithelial brushings, and bronchoalveolar lavage were obtained from subjects with asthma and normal subjects from the Severe Asthma Research Program (N 5 199). Tryptase, chymase, and carboxypeptidase A (CPA)3 were used to identify total MC (MC Tot ) and the MC TC subset (MCs positive for both tryptase and chymase) using immunostaining and quantitative real-time polymerase chain reaction. Lavage was analyzed for tryptase and prostaglandin D2 (PGD2) by ELISA. Measurements and Main Results: Submucosal MC Tot (tryptase-positive by immunostaining) numbers were highest in ''mild asthma/no inhaled corticosteroid (ICS) therapy'' subjects and decreased with greater asthma severity (P 5 0.002). In contrast, MC TC (chymasepositive by immunostaining) were the predominant (MC TC /MC Tot . 50%) MC phenotype in SA (overall P 5 0.005). Epithelial MC Tot were also highest in mild asthma/no ICS, but were not lower in SA. Instead, they persisted and were predominantly MC TC . Epithelial CPA3 and tryptase mRNA supported the immunostaining data (overall P 5 0.008 and P 5 0.02, respectively). Lavage PGD2 was higher in SA than in other steroid-treated groups (overall P 5 0.02), whereas tryptase did not differentiate the groups. In statistical models, PGD2 and MC TC /MC Tot predicted SA. Conclusions: Severe asthma is associated with a predominance of MC TC in the airway submucosa and epithelium. Activation of those MC TC may contribute to the increases in PGD2 levels. The data suggest an altered and active MC population contributes to SA pathology.

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Section: Discussionmentioning

confidence: 99%

Mast Cell Phenotype, Location, and Activation in Severe Asthma

Balzar¹,

Fajt²,

Comhair³

et al. 2011

Am J Respir Crit Care Med

269

247

View full text Add to dashboard Cite

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“…Chemokines induce B cell Ab class switching (33). In addition, IL-13 is a potent inducer of chemokines (eotaxins) in airway epithelial cells (31,34) and current models suggest that coordinated interactions between IL-13 and chemokines are importantly involved in the pathogenesis of asthma (35). Increased expression of cytokine and chemokine mRNA is likely the consequence of increased activity of transcription factors.…”

Section: Discussionmentioning

confidence: 99%

Increased Expression of Genes Linked to FcεRI Signaling and to Cytokine and Chemokine Production in Lyn-Deficient Mast Cells

Hernandez-Hansen

Bard

Tarleton

et al. 2005

The Journal of Immunology

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Cross-linking the high-affinity IgE receptor, FcεRI, on mast cells activates signaling pathways leading to the release of preformed inflammatory mediators and the production of cytokines and chemokines associated with allergic disorders. Bone marrow-derived mast cells (BMMCs) from Lyn-deficient (Lyn−/−) mice are hyperresponsive to FcεRI cross-linking with multivalent Ag. Previous studies linked the hyperresponsive phenotype in part to increased Fyn kinase activity and reduced SHIP phosphatase activity in the Lyn−/− BMMCs in comparison with wild-type (WT) cells. In this study, we compared gene expression profiles between resting and Ag-activated WT and Lyn−/− BMMCs to identify other factors that may contribute to the hyperresponsiveness of the Lyn−/− cells. Among genes implicated in the positive regulation of FcεRI signaling, mRNA for the tyrosine kinase, Fyn, and for several proteins contributing to calcium regulation are more up-regulated following Ag stimulation in Lyn−/− BMMCs than in WT BMMCs. Conversely, mRNA for the low-affinity IgG receptor (FcγRIIB), implicated in negative regulation of FcεRI-mediated signaling, is more down-regulated in Ag-stimulated Lyn−/− BMMCs than in WT BMMCs. Genes coding for proinflammatory cytokines and chemokines (IL-4, IL-6, IL-13, CSF, CCL1, CCL3, CCL5, CCL7, CCL9, and MIP1β)are all more highly expressed in Ag-stimulated Lyn−/− mast cells than in WT cells. These microarray data identify Lyn as a negative regulator in Ag-stimulated BMMCs of the expression of genes linked to FcεRI signaling and also to the response pathways that lead to allergy and asthma.

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“…Although regarded as a principal mediator of eosinophil chemotaxis, CCR3 antagonists have demonstrated the ability to provide mast cell stabilization and to inhibit both the early and late-phase of allergic inflammation in the mouse conjunctiva [118,130,131]. CCR3 antagonists are at various stages of development [132].…”

Section: Cell Membrane Targetsmentioning

confidence: 99%

The mast cell and allergic diseases: role in pathogenesis and implications for therapy

Brown

Wilson

Metcalfe

2007

Clin Experimental Allergy

239

184

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SummaryMast cells have long been recognized for their role in the genesis of allergic inflammation; and more recently for their participation in innate and acquired immune responses. Mast cells reside within tissues including the skin and mucosal membranes, which interface with the external environment; as well as being found within vascularized tissues next to nerves, blood vessels and glandular structures. Mast cells have the capability of reacting both within minutes and over hours to specific stimuli, with local and systemic effects. Mast cells express the high affinity IgE receptor (FceRI) and upon aggregation of FceRI by allergen-specific IgE, mast cells release and generate biologically active preformed and newly synthesized mediators which are involved in many aspects of allergic inflammation. While mast cells have been well documented to be essential for acute allergic reactions, more recently the importance of mast cells in reacting through pattern recognition receptors in innate immune responses has become recognized. Moreover, as our molecular understanding of the mast cell has evolved, novel targets for modulation have been identified with promising therapeutic potential.

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CC Chemokine Receptor 3 Mobilizes to the Surface of Human Mast Cells and Potentiates Immunoglobulin E–Dependent Generation of Interleukin 13

Cited by 52 publications

References 33 publications

Mast Cell Phenotype, Location, and Activation in Severe Asthma

Mast Cell Phenotype, Location, and Activation in Severe Asthma

Increased Expression of Genes Linked to FcεRI Signaling and to Cytokine and Chemokine Production in Lyn-Deficient Mast Cells

The mast cell and allergic diseases: role in pathogenesis and implications for therapy

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