IgE receptor of mast cells signals mediator release and inflammation via adaptor protein 14-3-3ζ - 08/09/23
, Jessica Chao, BSc a, Carl Coolen, BSc a, Harshita Pant, BMBS, PhD a, c, Anita Kral, BSc a, William Smith, MBBS, PhD b, Quenten Schwarz, PhD a, Michele A. Grimbaldeston, PhD a, ∗, Stuart Pitson, PhD a, Angel F. Lopez, MBBS, PhD a, c, Joanna Woodcock, PhD a, Damon J. Tumes, PhD a, ⁎ 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 numéro
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