IL-3 but not monomeric IgE regulates FcϵRI levels and cell survival in primary human basophils article

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.