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

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....

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Autores principales:	Edwin Leong, Zheng Pang, Andrew W. Stadnyk, Tong-Jun Lin
Formato:	article
Lenguaje:	EN
Publicado:	Karger Publishers 2021
Materias:	allergy allergic inflammation calcineurin degranulation vascular permeability Medicine R Internal medicine RC31-1245
Acceso en línea:	https://doaj.org/article/3a24870f55f54c1884bbd465257c0501
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spelling	oai:doaj.org-article:3a24870f55f54c1884bbd465257c05012021-12-02T12:40:22ZCalcineurin Aα Contributes to IgE-Dependent Mast-Cell Mediator Secretion in Allergic Inflammation1662-811X1662-812810.1159/000520040https://doaj.org/article/3a24870f55f54c1884bbd465257c05012021-11-01T00:00:00Zhttps://www.karger.com/Article/FullText/520040https://doaj.org/toc/1662-811Xhttps://doaj.org/toc/1662-8128Mast 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 (CnAα−/−) 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 CnAα−/− 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 CnAα contributes to the release of preformed mediators and newly synthesized mediators from FcϵRI-mediated activation of MCs, and this regulation includes NF-κB signaling.Edwin LeongZheng PangAndrew W. StadnykTong-Jun LinKarger Publishersarticleallergyallergic inflammationcalcineurindegranulationvascular permeabilityMedicineRInternal medicineRC31-1245ENJournal of Innate Immunity, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	allergy allergic inflammation calcineurin degranulation vascular permeability Medicine R Internal medicine RC31-1245
spellingShingle	allergy allergic inflammation calcineurin degranulation vascular permeability Medicine R Internal medicine RC31-1245 Edwin Leong Zheng Pang Andrew W. Stadnyk Tong-Jun Lin Calcineurin Aα Contributes to IgE-Dependent Mast-Cell Mediator Secretion in Allergic Inflammation
description	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 (CnAα−/−) 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 CnAα−/− 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 CnAα contributes to the release of preformed mediators and newly synthesized mediators from FcϵRI-mediated activation of MCs, and this regulation includes NF-κB signaling.
format	article
author	Edwin Leong Zheng Pang Andrew W. Stadnyk Tong-Jun Lin
author_facet	Edwin Leong Zheng Pang Andrew W. Stadnyk Tong-Jun Lin
author_sort	Edwin Leong
title	Calcineurin Aα Contributes to IgE-Dependent Mast-Cell Mediator Secretion in Allergic Inflammation
title_short	Calcineurin Aα Contributes to IgE-Dependent Mast-Cell Mediator Secretion in Allergic Inflammation
title_full	Calcineurin Aα Contributes to IgE-Dependent Mast-Cell Mediator Secretion in Allergic Inflammation
title_fullStr	Calcineurin Aα Contributes to IgE-Dependent Mast-Cell Mediator Secretion in Allergic Inflammation
title_full_unstemmed	Calcineurin Aα Contributes to IgE-Dependent Mast-Cell Mediator Secretion in Allergic Inflammation
title_sort	calcineurin aα contributes to ige-dependent mast-cell mediator secretion in allergic inflammation
publisher	Karger Publishers
publishDate	2021
url	https://doaj.org/article/3a24870f55f54c1884bbd465257c0501
work_keys_str_mv	AT edwinleong calcineurinaacontributestoigedependentmastcellmediatorsecretioninallergicinflammation AT zhengpang calcineurinaacontributestoigedependentmastcellmediatorsecretioninallergicinflammation AT andrewwstadnyk calcineurinaacontributestoigedependentmastcellmediatorsecretioninallergicinflammation AT tongjunlin calcineurinaacontributestoigedependentmastcellmediatorsecretioninallergicinflammation
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Calcineurin Aα Contributes to IgE-Dependent Mast-Cell Mediator Secretion in Allergic Inflammation

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