4.8 Article

The Inhibitory Receptor Siglec-8 Interacts With FcεRI and Globally Inhibits Intracellular Signaling in Primary Mast Cells Upon Activation

Journal

FRONTIERS IN IMMUNOLOGY
Volume 13, Issue -, Pages -

Publisher

FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2022.833728

Keywords

mast cells; IgE receptor; Siglec-8; intracellular signaling; proteomics

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Funding

  1. biorender.com

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This study reveals the inhibitory effect of Siglec-8 mAb on MC activity. Siglec-8 regulates Fc epsilon RI-induced phosphorylation events through phosphatase recruitment and interaction with Fc epsilon RI gamma, resulting in global inhibition of MCs.
Immunomodulation of mast cell (MC) activity is warranted in allergic and inflammatory diseases where MCs have a central role in pathogenesis. Targeting Siglec-8, an inhibitory receptor on MCs and eosinophils, has shown promising activity in preclinical and clinical studies. While the intracellular pathways that regulate Siglec-8 activity in eosinophils have been well studied, the signaling mechanisms that lead to MC inhibition have not been fully elucidated. Here, we evaluate the intracellular signaling pathways of Siglec-8-mediated inhibition in primary MCs using an anti-Siglec-8 monoclonal antibody (mAb). Phospho-proteomic profiling of Fc epsilon RI-activated MCs revealed Siglec-8 mAb-treatment globally inhibited proximal and downstream kinases, leading to attenuated MC activation and degranulation. In fact, Siglec-8 was found to directly interact with Fc epsilon RI signaling molecules. Siglec-8 inhibition was dependent on both cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIMs) that interact with the SH2 containing protein phosphatase Shp-2 upon Siglec-8 phosphorylation. Taken together, these data support a model in which Siglec-8 regulates proximal Fc epsilon RI-induced phosphorylation events through phosphatase recruitment and interaction with Fc epsilon RI gamma, resulting in global inhibition of MCs upon Siglec-8 mAb engagement.

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