Antipruritic effect of ursolic acid through MRGPRX2/MrgprB2-dependent inhibition of mast cell degranulation and reduced TSLP production

• Published in: European journal of pharmacology Vol. 981; p. 176896
• Main Authors: Cha, Jieun, Ryu, Juhee, Rawal, Diwas, Lee, Wook-Joo, Shim, Won-Sik
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 15.10.2024
• Subjects: Mast cell degranulation; MrgprB2; MRGPRX2; Pruritus; TSLP; Ursolic acid; Ursolic acid; Pruritus; TSLP; MrgprB2; MRGPRX2; Mast cell degranulation
• ISSN: 0014-2999; 1879-0712; 1879-0712
• DOI: 10.1016/j.ejphar.2024.176896

Ursolic acid (UA), a pentacyclic triterpene, exhibits diverse pharmacological effects, including potential treatment for allergic diseases. It downregulates thymic stromal lymphopoietin (TSLP) and disrupts mast cell signaling pathways. However, the exact molecular mechanism by which UA interferes with mast cell action remains unclear. Therefore, the current study aimed to uncover molecular entities underlying the effect of UA on mast cells and its potential antipruritic effect, specifically investigating its modulation of key molecules such as TRPV4, PAR2, and MRGPRX2, which are involved in TSLP regulation and sensation. Calcium imaging experiments revealed that UA pretreatment significantly suppressed MRGPRX2 activation (and its mouse orthologue MrgprB2), a G protein-coupled receptor predominantly expressed in mast cells. Molecular docking predictions suggested potential interactions between UA and MRGPRX2/MrgprB2. UA pretreatment also reduced mast cell degranulation through MRGPRX2 and MrgprB2-dependent mechanisms. In a dry skin mouse model, UA administration decreased tryptase and TSLP production in the skin, and diminished TSLP response in the sensory neurons. While PAR2 and TRPV4 activation enhances TSLP production, UA did not inhibit their activity. Notably, UA attenuated compound 48/80-induced scratching behaviors in mice and suppressed spontaneous scratching in a dry skin model. The present study confirms the effective inhibition of UA on MRGPRX2/MrgprB2, leading to reduced mast cell degranulation and suppressed scratching behaviors. These findings highlight the potential of UA as an antipruritic agent for managing various allergy- or itch-related conditions. [Display omitted] •UA interferes with the activity of MRGPRX2/MrgprB2, reducing mast cell degranulation.•UA inhibits TSLP-related itch signaling pathway without affecting TRPV4 and PAR2 in keratinocytes.•UA alleviates scratching induced by MRGPRX2/MrgprB2 agonists, suggesting its antipruritic potential.