Ursolic acid attenuates pseudo-allergic reactions via reducing MRGPRX2-mediated mast cell degranulation

Mas-related G protein-coupled receptor X2 (MRGPRX2) is a newly identified receptor on mast cells that contribute to IgE-independent pseudo-allergy. Ursolic acid (UA), a pentacyclic triterpenoid, has been reported for its anti-allergy effects. However, the protective mechanism against pseudo-allergic reactions remains unclear. This study aims to investigate the effects of UA on pseudo-allergic reactions both in vivo and in vitro, focusing on the therapeutical mechanism underlying its effect on mast cells. In present study, UA reduced degranulation and chemokines production induced by MRGPRX2 agonists, including compound 48/80 (C48/80) and substance P (SP), in LAD2 cells in vitro. UA also alleviated C48/80 and SP-induced systemic anaphylaxis and passive cutaneous anaphylaxis (PCA) in vivo. Furthermore, UA demonstrated strong binding affinity to the MRGPRX2 protein, leading to a decrease in calcium influx in both LAD2 cells and MRGPRX2-HEK293 cells stimulated with C48/80 and SP. Moreover, UA effectively suppressed phosphorylation levels within phospholipase C-γ (PLCγ) pathway and nuclear factor kappa-B (NF-κB) pathway of MRGPRX2 downstream proteins. Our findings indicated that UA exerts an attenuating effect in pseudo-allergic reactions by suppressing MRGPRX2-mediated mast cell activation, targeting PLCγ pathway and NF-κB pathway. These results suggest that UA may serve as a promising therapeutic agent for MRGPRX2-dependent pseudo-allergic reactions.