MRGPRX2 Mediates Mast Cell-Induced Endometriosis Pain Through the Sensitization of Sensory Neurons via Histamine/HRH1/TRPV1 Signaling Pathway.

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.