Yan Ping-Ping, Huang Ting-Ting, Liu Si-Yu, Attiogbe Mawusse K I, Liu Yan-Ni, Shen Fan-Qi, Mi Yan-Ni, Cao Yong-Xiao
Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, China.
Department of Pharmacology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, 710061, China; College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, 712046, China.
Immunol Lett. 2024 Dec;270:106934. doi: 10.1016/j.imlet.2024.106934. Epub 2024 Oct 10.
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.
Mas相关G蛋白偶联受体X2（MRGPRX2）是肥大细胞上新发现的一种受体，它参与非IgE依赖的假性过敏反应。熊果酸（UA）是一种五环三萜类化合物，其抗过敏作用已见报道。然而，其针对假性过敏反应的保护机制尚不清楚。本研究旨在探讨UA在体内和体外对假性过敏反应的影响，重点关注其对肥大细胞作用的治疗机制。在本研究中，UA在体外可减少MRGPRX2激动剂（包括化合物48/80（C48/80）和P物质（SP））诱导的LAD2细胞脱颗粒和趋化因子产生。UA在体内还可减轻C48/80和SP诱导的全身过敏反应和被动皮肤过敏反应（PCA）。此外，UA对MRGPRX2蛋白表现出很强的结合亲和力，导致在用C48/80和SP刺激的LAD2细胞和MRGPRX2-HEK293细胞中钙内流减少。而且，UA有效抑制了MRGPRX2下游蛋白磷脂酶C-γ（PLCγ）途径和核因子κB（NF-κB）途径内的磷酸化水平。我们的研究结果表明，UA通过抑制MRGPRX2介导的肥大细胞活化，靶向PLCγ途径和NF-κB途径，对假性过敏反应发挥减轻作用。这些结果提示，UA可能是治疗MRGPRX2依赖性假性过敏反应的一种有前景的治疗药物。
