Calcineurin Aα Contributes to IgE-Dependent Mast-Cell Mediator Secretion in Allergic Inflammation

Abstract

Mast cells (MCs) are key mediators of allergic inflammation through the activation of cross-linked immunoglobulin E (IgE) bound to the high-affinity IgE receptor (FcϵRI) on the cell surface, leading to the release of biologically potent mediators, either from preformed granules or newly synthesized. Pharmacological inhibitors have been developed to target a key signaling protein phosphatase in this pathway, calcineurin, yet there is a lack of genetic and definitive evidence for the various isoforms of calcineurin subunits in FcϵRI-mediated responses. In this study, we hypothesized that deficiency in the calcineurin Aα isoform will result in a decreased allergic immune response by the MCs. In a model of passive cutaneous anaphylaxis, there was a reduction in vascular permeability in MC-deficient mouse tissues reconstituted with calcineurin subunit A (CnAα) gene-knockout (<i>CnAα</i><sup>−/−</sup>) MCs, and in vitro experiments identified a significant reduction in release of preformed mediators from granules. Furthermore, released levels of de novo synthesized cytokines were reduced upon FcϵRI activation of <i>CnAα</i><sup>−/−</sup> MCs in vitro. Characterizing the mechanisms associated with this deficit response, we found a significant impairment of nuclear factor of kappa light polypeptide gene enhancer in B cell phosphorylation and impaired nuclear factor kappa-light-chain-enhancer of activated B-cell inhibitor alpha (NF-κB) activation. Thus, we concluded that <i>CnAα</i> contributes to the release of preformed mediators and newly synthesized mediators from FcϵRI-mediated activation of MCs, and this regulation includes NF-κB signaling.

Exploration of Efficacy and Mechanism of 0.05% Cyclosporine Eye Drops (II) Monotherapy in Allergic Conjunctivitis-associated Dry Eye

“…7 A recent study in mice suggested that calcineurin subunit A (CnAα) is involved in the early phases of mast cell-driven allergy reactions, and its de ciency resulted in the decrease of degranulation and in ammatory cytokines secretion in allergic responses. 22 According to these studies, we hypothesize that CsA may be effective against ACDE.…”

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

“…Many components involved in this process heavily rely on the intracellular calcium concentrations that are refilled by the efflux of ER calcium and influx of extracellular calcium. For example, calcineurin Aα that contributes to the release of allergic mediators in activated mast cells is calcium-dependent [71]. The calcium sensor, cation channels, and calcium-binding proteins (e.g., S100) are all involved in maintaining the intracellular calcium concentrations (Fig.…”