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

• DOI: 10.3389/fimmu.2022.833728
• Publication Date: 2022-01-28T08:57:08Z
• Authors: Wouter Korver; Alan Wong; Simon Gebremeskel; Gian Luca Negri; Julia Schanin; Katherine Chang; John Leung; Zachary Benet; Thuy Luu; Emily C. Brock; Kenneth Luehrsen; Alan Xu; Bradford A. Young...
• Keywords: SIGLEC; LYN

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