IgE receptor of mast cells signals mediator release and inflammation via adaptor protein 14-3-3ζ

• DOI: 10.1016/j.jaci.2023.04.011
• Publication Date: 2023-04-29T05:55:29Z
• Authors: Kwok Ho Yip; Jessica Chao; Carl Coolen; Harshita Pant; Anita Kral; William Smith; Quenten Schwarz; Michele A. Grimba...; Stuart Pitson; Angel F. Lopez; Joanna Woodcock; Damon J. Tumes
• Keywords: Inflammation; Receptors, IgE; Signal Transducing; Adaptor Proteins; mast cells; Immunoglobulin E; Cell Degranulation; 3. Good health; FcεRI signaling; Mice; 14-3-3 Proteins; Receptors; anaphylaxis; Humans; Animals; IgE; Mast Cells; Anaphylaxis; 14-3-3; adaptor protein; nasal polyp; Adaptor Proteins, Signal Transducing

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.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.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.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.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.