IgE receptor of mast cells signals mediator release and inflammation via adaptor protein 14-3-3ζ - 08/09/23
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Abstract |
Background |
Mast cells (MCs) are tissue-resident immune cells that mediate IgE-dependent allergic responses. Downstream of FcεRI, an intricate network of receptor-specific signaling pathways and adaptor proteins govern MC function. The 14-3-3 family of serine-threonine phosphorylation–dependent adapter proteins are known to organize intracellular signaling. However, the role of 14-3-3 in IgE-dependent activation remains poorly defined.
Objective |
We sought to determine whether 14-3-3 proteins are required for IgE-dependent MC activation and whether 14-3-3 is a viable target for the treatment of MC-mediated inflammatory diseases.
Methods |
Genetic manipulation of 14-3-3ζ expression in human and mouse MCs was performed and IgE-dependent mediator release assessed. Pharmacologic inhibitors of 14-3-3 and 14-3-3ζ knockout mice were used to assess 14-3-3ζ function in a MC-dependent in vivo passive cutaneous anaphylaxis (PCA) model of allergic inflammation. Expression and function of 14-3-3ζ were assessed in human nasal polyp tissue MCs.
Results |
IgE-dependent mediator release from human MCs was decreased by 14-3-3ζ knockdown and increased by 14-3-3ζ overexpression. Deletion of the 14-3-3ζ gene decreased IgE-dependent activation of mouse MCs in vitro and PCA responses in vivo. Furthermore, the 14-3-3 inhibitor, RB-11, which impairs dimerization of 14-3-3, inhibited cultured MC and polyp tissue MC activation and signaling downstream of the FcεRI receptor and dose-dependently attenuated PCA responses.
Conclusion |
IgE/FcεRI-mediated MC activation is positively regulated by 14-3-3ζ. We identify a critical role for this p-Ser/Thr–binding protein in the regulation of MC FcεRI signaling and IgE-dependent immune responses and show that this pathway may be amenable to pharmacologic targeting.
Le texte complet de cet article est disponible en PDF.Key words : 14-3-3, adaptor protein, anaphylaxis, FcεRI signaling, IgE, mast cells, nasal polyp
Abbreviations used : BMCMC, DNP, ERK, HCMC, HMEM, HSA, LAMP1, MC, PCA, PI3K, PIPES, PPI, siRNA, WT
Plan
The last 2 authors contributed equally to this article, and both should be considered senior author. |
Vol 152 - N° 3
P. 725 - septembre 2023 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
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