IL-3 but not monomeric IgE regulates Fc\u03b5RI levels and cell survival in primary human basophils

Fabian Zellweger,Alexander Eggel,Clemens Andreas Dahinden,Peter Matthias Villiger,Daniel Brigger,Patrick Buschor,Gabriel Hobi

doi:10.1038/s41419-018-0526-9

Fabian Zellweger, Alexander Eggel + Show 5 more

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https://doi.org/10.1038/s41419-018-0526-9

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Abstract

Binding of allergen-specific IgE to its primary receptor FcεRI on basophils and mast cells represents a central event in the development of allergic diseases. The high-affinity interaction between IgE and FcεRI results in permanent sensitization of these allergic effector cells and critically regulates their release of pro-inflammatory mediators upon IgE cross-linking by allergens. In addition, binding of monomeric IgE has been reported to actively regulate FcεRI surface levels and promote survival of mast cells in the absence of allergen through the induction of autocrine cytokine secretion including interleukin-3 (IL-3). As basophils and mast cells share many biological commonalities we sought to assess the role of monomeric IgE binding and IL-3 signaling in FcεRI regulation and cell survival of primary human basophils. FcεRI cell surface levels and survival of isolated blood basophils were assessed upon addition of monomeric IgE or physiologic removal of endogenous cell-bound IgE with a disruptive IgE inhibitor by flow cytometry. We further determined basophil cell numbers in both low and high serum IgE blood donors and mice that are either sufficient or deficient for FcεRI. Ultimately, we investigated the effect of IL-3 on basophil surface FcεRI levels by protein and gene expression analysis. Surface levels of FcεRI were passively stabilized but not actively upregulated in the presence of monomeric IgE. In contrast to previous observations with mast cells, monomeric IgE binding did not enhance basophil survival. Interestingly, we found that IL-3 transcriptionally regulates surface levels of FcεRI in human primary basophils. Our data suggest that IL-3 but not monomeric IgE regulates FcεRI expression and cell survival in primary human basophils. Thus, blocking of IL-3 signaling in allergic effector cells might represent an interesting approach to diminish surface FcεRI levels and to prevent prolonged cell survival in allergic inflammation.

Highlights

Binding of allergen-specific immunoglobulin E (IgE) to its high-affinity receptor FcεRI expressed on basophils and mast cells is a central step in the induction of allergic hypersensitivity reactions[1]
Despite controversial findings with mast cells, we aimed to investigate the effect of monomeric IgE binding and IL3 signaling on FcεRI regulation and cell survival of human primary blood basophils in this study
Compared with incubation in medium the addition of exogenous IgE reduced the loss of FcεRI on basophils from both low (Fig. 1a) and high serum IgE (Fig. 1b) donors

Summary

Introduction

Binding of allergen-specific immunoglobulin E (IgE) to its high-affinity receptor FcεRI expressed on basophils and mast cells is a central step in the induction of allergic hypersensitivity reactions[1]. On these cells, FcεRI is expressed as a hetero-tetramer[2]. The membrane tetra-spanning β-chain (FcεRIβ), and the two identical disulfide-linked γchains (FcεRIγ) are not involved in the IgE interaction but are essential for receptor maturation, receptor surface transport, and the propagation of FcεRI-mediated signaling pathways[4]. Owing to the high-affinity interaction of IgE: FcεRI complexes basophils and mast cells are permanently sensitized with IgE and are ready to immediately respond to allergen challenge. Antigen-induced co-aggregation of receptor-bound IgE stimulates the release of prestored and de novo synthesized mediators that induce

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