Caffeic acid phenethyl ester inhibits pseudo-allergic reactions via inhibition of MRGPRX2/MrgprB2-dependent mast cell degranulation

Abstract

Mast cells play essential role in allergic reactionsthrough the process called mast cell degranulation. Recent studies have found that a basic secretagogue compound48/80 (C48/80) induces non-IgE-mediated mastcell degranulation via activation of human Mas-related Gprotein-coupled receptor X2 (MRGPRX2) and mouse MrgprB2. Although previous studies have revealed that caff eicacid (CA) and its derivatives possess anti-allergic eff ects viaIgE-dependent manner, it is largely elusive whether thesecompounds have impact on MRGPRX2/MrgprB2 to exertinhibitory eff ects. Therefore, the present study investigatedwhether CA as well as its derivatives – rosmarinic acid (RA)and caff eic acid phenethyl ester (CAPE) – has the abilityto inhibit the activity of MRGPRX2/MrgprB2 to evokepseudo-allergic eff ects. As a result, it was found that CAPEinhibits C48/80-induced activation of MRGPRX2/MrgprB2,but neither CA nor RA showed discernible inhibition. Furthermore,the β-hexosaminidase release assay showed thatCAPE inhibits mouse peritoneal mast cell degranulationin both IgE-dependent and MrgprB2-dependent manners. Additionally, mouse paw edema induced by C48/80 was dramaticallysuppressed by co-treatment of CAPE, suggestingthat CAPE possesses a protective eff ect on C48/80-evokedpseudo-allergic reactions. The pretreatment of CAPE also signifi cantly decreased scratching bouts of mice evokedby C48/80, demonstrating that CAPE also has an anti-pruriticeff ect. Therefore, these data implicate that CAPE cansuppress pseudo-allergic reactions evoked by C48/80 viaMrgprB2-dependent manner. Finally, molecular dockinganalysis showed that CAPE is predicted to bind to humanMRGPRX2 in the region where C48/80 also binds, implyingthat CAPE can be a competitive inhibitor of MRGPRX2. Inconclusion, it is found that CAPE has the ability to inhibitMRGPRX2/MrgprB2, leading to the prevention of mast celldegranulation and further to the alleviation of mast cell reactions. These results indicate that CAPE as a CA derivativecould be developed as a new protective agent that exerts dualinhibition of mast cell degranulation mediated by IgE andMRGPRX2/MrgprB2.