Mao Xinqi, Wang Jianzhang, Ding Shaojie, Guo Xinyue, Xu Xinxin, Xu Ping, Zhang Xinmei
Department of Gynecology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, People's Republic of China.
Zhejiang Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Hangzhou, People's Republic of China.
FASEB J. 2025 Jul 15;39(13):e70778. doi: 10.1096/fj.202501493R.
The studies on how mast cells mediate endometriosis pain are still limited. Mas-related G protein-coupled receptor member X2 (MRGPRX2), a receptor expressed on mast cells, participates in pain, inflammation, and itch. However, it is still unclear whether and how MRGPRX2 mediates endometriosis pain. Here, we found that the knockout of mast cells alleviated endometriosis-induced hyperalgesia. The density of MRGPRX2-positive mast cells was increased in endometriotic lesions. HBD-2 was secreted from endometriotic cells. Upon HBD-2 treatment, a significant increase in histamine release in the culture supernatant of HMC1.1 cells was detected, whereas no change in histamine levels was observed in the supernatant of MRGPRX2 KO cells. An incubation with histamine increased Ca2+ influx in DRG cells in vitro, whereas desloratadine reversed this process. In Mrgprb2-deficient endometriosis model mice, gene ablation effectively alleviated hyperalgesia and reduced the size of endometriotic lesions. Overall, MRGPRX2 mediates cell-induced endometriosis pain through sensory neurons sensitization via the histamine/HRH1/TRPV1 signaling pathway and can serve as a novel therapeutic target for endometriosis pain.
肥大细胞介导子宫内膜异位症疼痛的相关研究仍然有限。与 Mas 相关的 G 蛋白偶联受体成员 X2（MRGPRX2）是一种在肥大细胞上表达的受体，参与疼痛、炎症和瘙痒过程。然而，MRGPRX2 是否以及如何介导子宫内膜异位症疼痛仍不清楚。在此，我们发现敲除肥大细胞可减轻子宫内膜异位症诱导的痛觉过敏。在子宫内膜异位症病变中，MRGPRX2 阳性肥大细胞的密度增加。子宫内膜异位症细胞分泌人β-防御素-2（HBD-2）。用 HBD-2 处理后，检测到 HMC1.1 细胞培养上清液中的组胺释放显著增加，而在 MRGPRX2 基因敲除细胞的上清液中未观察到组胺水平的变化。在体外，与组胺孵育可增加背根神经节（DRG）细胞中的 Ca2+内流，而地氯雷他定可逆转这一过程。在 Mrgprb2 缺陷的子宫内膜异位症模型小鼠中，基因敲除有效地减轻了痛觉过敏并减小了子宫内膜异位症病变的大小。总体而言，MRGPRX2 通过组胺/组胺受体 1（HRH1）/瞬时受体电位香草酸亚型 1（TRPV1）信号通路使感觉神经元致敏，从而介导细胞诱导的子宫内膜异位症疼痛，并且可作为子宫内膜异位症疼痛的新型治疗靶点。
