Department of Physiology, Michigan State University, East Lansing, MI, United States.
Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC, United States.
Front Immunol. 2020 Jan 21;10:3143. doi: 10.3389/fimmu.2019.03143. eCollection 2019.
Mast cells are inflammatory immune cells that play an essential role in mediating allergic reactions in humans. It is well-known that mast cell activation is critically regulated by intracellular calcium ion (Ca) concentrations. MAS-related G-protein coupled receptor-X2 (MRGPRX2) is a G-protein coupled receptor (GPCR) expressed on mast cells that is activated by various ligands, including several FDA approved drugs; consequently, this receptor has been implicated in causing pseudo-allergic reactions in humans. MRGPRX2 activation leads to an increase in intracellular Ca levels; however, the Ca mobilizing mechanisms utilized by this receptor are largely unknown. Previous reports showed that store-operated Ca entry (SOCE) via the calcium sensor, stromal interaction molecule 1 (STIM1), regulates mast cell response induced by the high-affinity IgE receptor (FcεRI). In this study, using complementary pharmacologic and genetic ablation approaches we demonstrate that SOCE through STIM1 promotes MRGPRX2-induced human mast cell response . Importantly, SOCE also critically modulates MrgprB2 (mouse ortholog of human MRGPRX2) dependent inflammation in mouse models of pseudo-allergy. Collectively, our data suggests that MRGPRX2/MrgprB2 activation of mast cells is dependent on SOCE via STIM1, and further characterization of the MRGPRX2-SOCE-STIM1 pathway will lead to the identification of novel targets for the treatment of pseudo-allergic reactions in humans.
肥大细胞是炎症免疫细胞，在介导人类过敏反应中发挥着重要作用。众所周知，肥大细胞的激活受到细胞内钙离子（Ca）浓度的严格调控。MAS 相关 G 蛋白偶联受体-X2（MRGPRX2）是一种表达在肥大细胞上的 G 蛋白偶联受体（GPCR），可被多种配体激活，包括几种获得 FDA 批准的药物；因此，该受体与人类引起的假性过敏反应有关。MRGPRX2 的激活导致细胞内 Ca 水平升高；然而，该受体利用的 Ca 动员机制在很大程度上尚不清楚。先前的报告表明，通过钙传感器基质相互作用分子 1（STIM1）的储存操作 Ca 内流（SOCE）调节高亲和力 IgE 受体（FcεRI）诱导的肥大细胞反应。在这项研究中，我们使用互补的药理和遗传消融方法证明，通过 STIM1 的 SOCE 促进了 MRGPRX2 诱导的人肥大细胞反应。重要的是，SOCE 还严重调节了小鼠假性过敏模型中 MrgprB2（人 MRGPRX2 的小鼠同源物）依赖性炎症。总的来说，我们的数据表明，肥大细胞中 MRGPRX2/MrgprB2 的激活依赖于通过 STIM1 的 SOCE，进一步表征 MRGPRX2-SOCE-STIM1 途径将导致鉴定人类假性过敏反应的新治疗靶点。
