Resveratrol inhibits MRGPRX2-mediated mast cell activation via Nrf2 pathway

Mast cells (MCs) are crucial effectors in inflammation and allergic reactions. The Mas-related G-protein-coupled receptor X2 (MRGPRX2) was the MC-specific receptor and play a key role in IgE-independent allergic reactions. The activation of the Nuclear factor erythroid derived 2-related factor 2 (Nrf2) is involved in IgE-mediated MC degranulation. Resveratrol (Res) is a polyphenolic compound in red wine and has been reported to exert a variety of pharmacological effects. In the current study, we investigated the effect of Res in regulating MRGPRX2-mediated MC activation and its underlyingmechanism. We demonstrated that Res reduced compound 48/80 (C48/80)-induced calcium flux in MCs and inhibited MCs degranulation in vitro. Res also suppressed C48/80-induced hind paw extravasation, active systemic anaphylaxis, and MCs degranulation in mouse models of pseudo-allergy in vivo. Furthermore, PCR and immunohistochemistry assay suggest that Res up-regulates Nrf2 expression and Nrf2 inhibitor attenuates the protective effects of Res. In conclusion, Res exerts an inhibitory effect on MRGPRX2-mediated MCs activation by targeting Nrf2 pathway and may present a promising new therapeutic agent for the treatment of MRGPRX2-dependent anaphylactoid reactions.