Regulation of Trafficking and Signaling of the High Affinity IgE Receptor by Fc epsilon RI beta and the Potential Impact of Fc epsilon RI beta Splicing in Allergic Inflammation

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, Fc epsilon RI, 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 Fc epsilon RI structure and function, and describe established and emerging roles of the beta subunit of Fc epsilon RI (Fc epsilon RI beta) in regulating mast cell function and Fc epsilon RI trafficking and signaling. We discuss current approaches to target IgE and Fc epsilon RI signaling and emerging approaches that could target Fc epsilon RI beta specifically. We examine how alternative splicing of Fc epsilon RI beta alters protein function and how manipulation of splicing could be employed as a therapeutic approach. Targeting Fc epsilon RI directly and/or IgE binding to Fc epsilon RI are promising approaches to therapeutics for allergic inflammation. The characteristic role of Fc epsilon RI beta in both trafficking and signaling of the Fc epsilon RI receptor complex, the specificity to IgE-mediated activation pathways, and the preferential expression in mast cells and basophils, makes Fc epsilon RI beta an excellent, but challenging, candidate for therapeutic strategies in allergy and asthma, if targeting can be realized.