Department of Dermatology, Northwest Hospital, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China; Department of Dermatology, The Second Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, Baotou, Inner Mongolia, China.
Department of Dermatology, Northwest Hospital, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
Int Immunopharmacol. 2020 Apr;81:106258. doi: 10.1016/j.intimp.2020.106258. Epub 2020 Feb 7.
While imiquimod (IMQ) has been widely used in dermatology, its side effect manifested as dermatitis couldn't be ignored. However, the underlying mechanism has not been fully understood. Considering the clinical features of IMQ-related dermatitis similar to pseudo-allergic reaction and the presence of large numbers of mast cell in tissues treated with IMQ, the possibility that IMQ-related dermatitis mediated by mast cell-specific Mas-related G protein-coupled receptor X2 (MRGPRX2) should be addressed. To investigate the role of MRGPRX2 in vivo, MrgprB2, the mice homology of human MRGPRX2, was detected in IMQ-induced dermatitis mouse model. Histopathological changes including mast cell degranulation and footpad swelling were assayed in wild-type and MrgprB2 mice. The results showed that IMQ application induced dermatitis and footpad swelling with inflammatory cells infiltration plus mast cell activation in the skin of wild-type mice but reduced significantly in MrgprB2 mice. Further, compared to wild-type mice, serum histamine and inflammatory cytokine levels were compromised in MrgprB2 mice treated with IMQ, while the serum IgE level didn't change significantly. In vitro studies, levels of mediators released from murine peritoneal mast cells (MPMCs) after IMQ treatment were increased in a dose-dependent manner, which were much mild in MPMCs from MrgprB2 mice. Intracellular Ca concentration was increased in a dose dependent manner after IMQ treatment both in MrgprB2-HEK293 and MRGPRX2-HEK293 cells. Moreover, β-hexosaminidase released after IMQ treatment was blocked by siRNA directed at the MRGPRX2 receptor in LAD2 cells. In summary, MrgprB2 /MRGPRX2 mediate mast cell activation and participate in IMQ-related dermatitis.
虽然咪喹莫特 (IMQ) 在皮肤病学中得到了广泛应用，但它表现出的副作用——皮炎不容忽视。然而，其潜在的机制尚未完全被理解。考虑到 IMQ 相关皮炎的临床特征类似于假性过敏反应，以及 IMQ 处理的组织中存在大量肥大细胞，IMQ 相关皮炎可能由肥大细胞特异性 Mas 相关 G 蛋白偶联受体 X2 (MRGPRX2) 介导。为了研究 MRGPRX2 在体内的作用，在 IMQ 诱导的皮炎小鼠模型中检测了 MrgprB2，即人类 MRGPRX2 的同源物。在野生型和 MrgprB2 小鼠中，检测了包括肥大细胞脱颗粒和足垫肿胀在内的组织学变化。结果显示，IMQ 应用诱导了皮炎和足垫肿胀，伴有野生型小鼠皮肤中炎症细胞浸润和肥大细胞激活，但在 MrgprB2 小鼠中明显减少。此外，与野生型小鼠相比，IMQ 处理的 MrgprB2 小鼠的血清组胺和炎症细胞因子水平降低，但血清 IgE 水平无明显变化。体外研究显示，IMQ 处理后，来自小鼠腹腔肥大细胞 (MPMCs) 的介质释放水平呈剂量依赖性增加，而来自 MrgprB2 小鼠的 MPMCs 则明显减少。IMQ 处理后，MrgprB2-HEK293 和 MRGPRX2-HEK293 细胞中的细胞内 Ca2+浓度呈剂量依赖性增加。此外，在 LAD2 细胞中，针对 MRGPRX2 受体的 siRNA 可阻断 IMQ 处理后β-己糖胺酶的释放。综上所述，MrgprB2/MRGPRX2 介导肥大细胞激活并参与 IMQ 相关皮炎。
