scholarly journals Exon skipping of FcεRIβ eliminates expression of the high-affinity IgE receptor in mast cells with therapeutic potential for allergy

2016 ◽  
Vol 113 (49) ◽  
pp. 14115-14120 ◽  
Author(s):  
Glenn Cruse ◽  
Yuzhi Yin ◽  
Tomoki Fukuyama ◽  
Avanti Desai ◽  
Greer K. Arthur ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Cell Function ◽  
Specific Treatment ◽  
Exon Skipping ◽  
Allergic Diseases ◽  
Ige Receptor ◽  
High Affinity ◽  
High Affinity Ige Receptor

Allergic diseases are driven by activation of mast cells and release of mediators in response to IgE-directed antigens. However, there are no drugs currently available that can specifically down-regulate mast cell function in vivo when chronically administered. Here, we describe an innovative approach for targeting mast cells in vitro and in vivo using antisense oligonucleotide-mediated exon skipping of the β-subunit of the high-affinity IgE receptor (FcεRIβ) to eliminate surface high-affinity IgE receptor (FcεRI) expression and function, rendering mast cells unresponsive to IgE-mediated activation. As FcεRIβ expression is restricted to mast cells and basophils, this approach would selectively target these cell types. Given the success of exon skipping in clinical trials to treat genetic diseases such as Duchenne muscular dystrophy, we propose that exon skipping of FcεRIβ is a potential approach for mast cell-specific treatment of allergic diseases.

scholarly journals Mast cell activation is enhanced by Tim1:Tim4 interaction but not by Tim-1 antibodies

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 251
Author(s):  
Binh Phong ◽  
Lawrence P. Kane
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Signaling Pathways ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Immune Cell ◽  
Allergic Diseases ◽  
Mast Cell Activation ◽  
High Affinity Ige Receptor

Polymorphisms in theT cell (or transmembrane) immunoglobulin and mucin domain 1(TIM-1) gene, particularly in the mucin domain, have been associated with atopy and allergic diseases in mice and human. Genetic- and antibody-mediated studies revealed that Tim-1 functions as a positive regulator of Th2 responses, while certain antibodies to Tim-1 can exacerbate or reduce allergic lung inflammation. Tim-1 can also positively regulate the function of B cells, NKT cells, dendritic cells and mast cells. However, the precise molecular mechanisms by which Tim-1 modulates immune cell function are currently unknown. In this study, we have focused on defining Tim-1-mediated signaling pathways that enhance mast cell activation through the high affinity IgE receptor (FceRI). Using a Tim-1 mouse model lacking the mucin domain (Tim-1Dmucin), we show for the first time that the polymorphic Tim-1 mucin region is dispensable for normal mast cell activation. We further show that Tim-4 cross-linking of Tim-1 enhances select signaling pathways downstream of FceRI in mast cells, including mTOR-dependent signaling, leading to increased cytokine production but without affecting degranulation.

scholarly journals Mast cell activation is enhanced by Tim1:Tim4 interaction but not by Tim-1 antibodies

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 251
Author(s):  
Binh Phong ◽  
Lawrence P. Kane
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Signaling Pathways ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Immune Cell ◽  
Allergic Diseases ◽  
Mast Cell Activation ◽  
High Affinity Ige Receptor

Polymorphisms in theT cell (or transmembrane) immunoglobulin and mucin domain 1(TIM-1) gene, particularly in the mucin domain, have been associated with atopy and allergic diseases in mice and human. Genetic- and antibody-mediated studies revealed that Tim-1 functions as a positive regulator of Th2 responses, while certain antibodies to Tim-1 can exacerbate or reduce allergic lung inflammation. Tim-1 can also positively regulate the function of B cells, NKT cells, dendritic cells and mast cells. However, the precise molecular mechanisms by which Tim-1 modulates immune cell function are currently unknown. In this study, we have focused on defining Tim-1-mediated signaling pathways that enhance mast cell activation through the high affinity IgE receptor (FceRI). Using a Tim-1 mouse model lacking the mucin domain (Tim-1Dmucin), we show for the first time that the polymorphic Tim-1 mucin region is dispensable for normal mast cell activation. We further show that Tim-4 cross-linking of Tim-1 enhances select signaling pathways downstream of FceRI in mast cells, including mTOR-dependent signaling, leading to increased cytokine production but without affecting degranulation.

scholarly journals Regulation of Trafficking and Signaling of the High Affinity IgE Receptor by FcεRIβ and the Potential Impact of FcεRIβ Splicing in Allergic Inflammation

2022 ◽  
Vol 23 (2) ◽  
pp. 788
Author(s):  
Greer K. Arthur ◽  
Glenn Cruse
Keyword(s):  
Mast Cells ◽  
Cell Function ◽  
Allergic Inflammation ◽  
Receptor Complex ◽  
Ige Receptor ◽  
Preferential Expression ◽  
High Affinity ◽  
Proinflammatory Mediators ◽  
Ige Mediated ◽  
High Affinity Ige Receptor

Mast cells are tissue-resident immune cells that function in both innate and adaptive immunity through the release of both preformed granule-stored mediators, and newly generated proinflammatory mediators that contribute to the generation of both the early and late phases of the allergic inflammatory response. Although mast cells can be activated by a vast array of mediators to contribute to homeostasis and pathophysiology in diverse settings and contexts, in this review, we will focus on the canonical setting of IgE-mediated activation and allergic inflammation. IgE-dependent activation of mast cells occurs through the high affinity IgE receptor, FcεRI, which is a multimeric receptor complex that, once crosslinked by antigen, triggers a cascade of signaling to generate a robust response in mast cells. Here, we discuss FcεRI structure and function, and describe established and emerging roles of the β subunit of FcεRI (FcεRIβ) in regulating mast cell function and FcεRI trafficking and signaling. We discuss current approaches to target IgE and FcεRI signaling and emerging approaches that could target FcεRIβ specifically. We examine how alternative splicing of FcεRIβ alters protein function and how manipulation of splicing could be employed as a therapeutic approach. Targeting FcεRI directly and/or IgE binding to FcεRI are promising approaches to therapeutics for allergic inflammation. The characteristic role of FcεRIβ in both trafficking and signaling of the FcεRI receptor complex, the specificity to IgE-mediated activation pathways, and the preferential expression in mast cells and basophils, makes FcεRIβ an excellent, but challenging, candidate for therapeutic strategies in allergy and asthma, if targeting can be realized.

scholarly journals Negative Regulation of Immunoglobulin E–dependent Allergic Responses by Lyn Kinase

2004 ◽  
Vol 199 (11) ◽  
pp. 1491-1502 ◽  
Author(s):  
Sandra Odom ◽  
Gregorio Gomez ◽  
Martina Kovarova ◽  
Yasuko Furumoto ◽  
John J. Ryan ◽  
...  
Keyword(s):  
Mast Cells ◽  
Negative Regulation ◽  
Negative Regulator ◽  
Cell Surface Expression ◽  
Ige Receptor ◽  
High Affinity ◽  
Fyn Kinase ◽  
Lyn Kinase ◽  
High Affinity Ige Receptor

A role for Lyn kinase as a positive regulator of immunoglobulin (Ig)E-dependent allergy has long been accepted. Contrary to this belief, Lyn kinase was found to have an important role as a negative regulator of the allergic response. This became apparent from the hyperresponsive degranulation of lyn−/− bone marrow–derived mast cells, which is driven by hyperactivation of Fyn kinase that occurs, in part, through the loss of negative regulation by COOH-terminal Src kinase (Csk) and the adaptor, Csk-binding protein. This phenotype is recapitulated in vivo as young lyn−/− mice showed an enhanced anaphylactic response. In vivo studies also demonstrated that as lyn−/− mice aged, their serum IgE increased as well as occupancy of the high affinity IgE receptor (FcεRI). This was mirrored by increased circulating histamine, increased mast cell numbers, increased cell surface expression of the high affinity IgE receptor (FcεRI), and eosinophilia. The increased IgE production was not a consequence of increased Fyn kinase activity in lyn−/− mice because both lyn−/− and lyn−/− fyn−/− mice showed high IgE levels. Thus, lyn−/− mice and mast cells thereof show multiple allergy-associated traits, causing reconsideration of the possible efficacy in therapeutic targeting of Lyn in allergic disease.

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.

scholarly journals Extracellular Signal-Regulated Kinases 1 and 2 Phosphorylate Gab2 To Promote a Negative-Feedback Loop That Attenuates Phosphoinositide 3-Kinase/Akt Signaling

2017 ◽  
Vol 37 (7) ◽  
Author(s):  
Xiaocui Zhang ◽  
Geneviève Lavoie ◽  
Antoine Méant ◽  
Léo Aubert ◽  
Marie Cargnello ◽  
...  
Keyword(s):  
Mast Cells ◽  
Negative Feedback ◽  
Feedback Loop ◽  
Akt Signaling ◽  
Negative Feedback Loop ◽  
Ige Receptor ◽  
High Affinity ◽  
Extracellular Signal ◽  
Phosphoinositide 3 Kinase ◽  
High Affinity Ige Receptor

ABSTRACT The scaffolding adapter protein Gab2 (Grb2-associated binder) promotes cell proliferation, survival, and motility by engaging several signaling pathways downstream of growth factor and cytokine receptors. In particular, Gab2 plays essential roles in mast cells, as it is required for phosphoinositide 3-kinase (PI3K) activation in response to Kit and the high-affinity IgE receptor. While the positive role of Gab2 in PI3K signaling is well documented, very little is known about the mechanisms that attenuate its function. Here we show that Gab2 becomes phosphorylated on multiple proline-directed sites upon stimulation of the Ras/extracellular signal-regulated kinase (ERK) signaling pathway. We demonstrate that ERK1 and ERK2 interact with Gab2 via a novel docking motif, which is required for subsequent Gab2 phosphorylation in response to ERK1/2 activation. We identified four ERK1/2-dependent phosphorylation sites in Gab2 that prevent the recruitment of the p85 regulatory subunit of PI3K. Using bone marrow-derived mast cells to study Gab2-dependent signaling, we found that the inhibition of ERK1/2 activity promotes Akt signaling in response to Kit and the high-affinity IgE receptor. Together, our results indicate that ERK1/2 participates in a negative-feedback loop that attenuates PI3K/Akt signaling in response to various agonists.

scholarly journals p85β regulatory subunit of class IA PI3 kinase negatively regulates mast cell growth, maturation, and leukemogenesis

Blood ◽  
2012 ◽  
Vol 119 (17) ◽  
pp. 3951-3961 ◽  
Author(s):  
Subha Krishnan ◽  
Raghuveer Singh Mali ◽  
Baskar Ramdas ◽  
Emily Sims ◽  
Peilin Ma ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Cell Function ◽  
Receptor Internalization ◽  
Regulatory Subunit ◽  
Growth Defects ◽  
Microphthalmia Transcription Factor ◽  
Carboxy Terminal

Abstract We show that loss of p85α inhibits the growth and maturation of mast cells, whereas loss of p85β enhances this process. Whereas restoring the expression of p85α in P85α−/− cells restores these functions, overexpression of p85β has the opposite effect. Consistently, overexpression of p85β in WT mast cells represses KIT-induced proliferation and IL-3–mediated maturation by inhibiting the expression of Microphthalmia transcription factor. Because p85α and p85β differ in their N-terminal sequences, chimeric proteins consisting of amino or carboxy-terminal of p85α and/or p85β do not rescue the growth defects of p85α−/− cells, suggesting cooperation between these domains for normal mast cell function. Loss of p85β impaired ligand induced KIT receptor internalization and its overexpression enhanced this process, partly because of increased binding of c-Cbl to p85β relative to p85α. In vivo, loss of p85β resulted in increased mast cells, and bone marrow transplantation of cells overexpressing p85β resulted in significant reduction in some tissue mast cells. Overexpression of p85β suppressed the growth of oncogenic KIT-expressing cells in vitro and prolonged the survival of leukemic mice in vivo. Thus, p85α and p85β differentially regulate SCF and oncogenic KIT-induced signals in myeloid lineage-derived mast cells.

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