Myricetin served as antagonist for negatively regulate MRGPRX2 mediated pseudo-allergic reactions through CD300f/SHP1/SHP2 phosphorylation

Background: Mas-related G protein-coupled receptor X2 (MRGPRX2) plays a vital role in mast cells (MCs) degranulation and pseudo-allergic reactions. Leukocyte mono-immunoglobulin-like receptor 3 (CD300f) can negatively regulate MCs degranulation. Identification of drug candidates which target CD300f represents a promising prospect in drug development. Myricetin is widely distributed in plants and has been reported to inhibit allergic reactions in OVA-induced murine models.Objective: This study aims to determine whether myricetin can activate CD300f to arrest MCs degranulation mediated by MRGPRX2. Results: Myricetin inhibited the allergic mediator and cytokine release triggered by MRGPRX2 in vivo and in vitro. Under C48/80 stimulation, the release of 13-hexosaminidase, TNF-alpha, IL-8 and MCP-1 in CD300f knockdown in LAD2 cells was significantly increased compared with NC-LAD2 cells. Myricetin displayed good structural affinity (KD = 7.21 x 10-5) with CD300f by SPR. Molecular docking results showed that hydrogen bonds were formed between myricetin and CD300f, indicating high binding ability (5.6653). Myricetin can upregulate the phosphorylation of SHP-1 and SHP-2 and dephosphorylation in the MRGPRX2 signaling pathway, involving PLC gamma 1, AKT, P38, and ERK1/2.Conclusion: In the present study, myricetin is identified as an exogenous ligand for CD300f, which negatively regulates MRGPRX2-mediated MCs activation via CD300f to inhibit MCs degranulation and pseudo-allergic reactions.

Automated summary

In this study, myricetin was identified as an exogenous ligand for CD300f, which negatively regulates MRGPRX2-mediated MCs activation to inhibit MCs degranulation and pseudo-allergic reactions.