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

Abstract

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.

Genetic/Environmental Contributions and Immune Dysregulation in Children with Atopic Dermatitis

“…102 FcεRIβ encodes a subunit of the high-affinity IgE receptor FcεRI and mediates trafficking and signaling of this receptor. 103 Meanwhile, ADAMTSL4 encodes a potential IgE-binding selfantigen in AD and has been linked to eosinophil counts, which are known to be elevated in AD. [104][105][106] Finally, CYSLTR1 encodes a receptor for cysteinyl leukotrienes; variants may predispose children to asthma and AD.…”

Potential Role of Moesin in Regulating Mast Cell Secretion

“…Even though the stimulus-response coupling pathway has been well delineated for activation of the high-affinity surface receptor for IgE (FcεRI) [42,102,103], and, more recently, of the low-affinity receptor for cationic peptides, Mas-Related G Protein-Coupled Receptor-X2 (MRGPRX2) [104][105][106][107][108], there is still a lack of understanding of the molecular events regulating secretion, whether by degranulation, selective release of mediators or any other mode of secretion (Table 1). The mode and extent of mast cell responsiveness ultimately depend on the interplay between stimulatory and inhibitory signaling pathways, such as CD300 [109,110] and Singlets [111], especially Siglec-7 [112], and the β subunit of FcεRI (FcεRIβ) [113].…”

New Mechanistic Advances in FcεRI-Mast Cell–Mediated Allergic Signaling

“…The FcεRI complex on human mast cell surface is a tetramer composed of one α subunit, one β-subunit, and 2 γ-subunits (αβγ2) [11,45,47]. Among these, the α-subunit has two extracellular Ig superfamily domains (α1 and α2), both of which are responsible for the ligand (Fc fragment of the IgE antibody) binding [10], while the β-and γ-subunits contain immunoreceptor tyrosine-based activation motifs (ITAMs) that provide binding sites for many intracellular signal molecules via their Sarcoma (SRC) homology 2 (SH2) domains [11,48,49].…”

“…Recent studies have shown that β-subunit hypofunction (by exon skipping) and hyperfunction (by an enhancer named MS4A4A) can either hamper or boost the development of allergic diseases, respectively [50,51]. Due to its core role, the FcεRIβ is a primary target of many therapeutic interventions for allergic diseases [49]. In addition, interaction of HDAC3 with a series of microRNAs can modulate the FcεRI activity and mediate passive anaphylaxis by deacetylating the histones [52].…”