P2X4 receptor mediates macrophage infiltration leading to endometriotic cyst epithelium proliferation and hyperalgesia in mouse model

OBJECTIVE: To evaluate the effects of a P2X4 receptor (P2X4R)-specific antagonist on murine endometriotic-like lesions and human endometriotic stromal cells. DESIGN: Experimental study using an in vivo mouse endometriosis model and in vitro primary culture of human endometriotic stromal cells. NC-2600, an antagonist of the P2X4 ionotropic ATP receptor (P2X4R), was orally administered to the mice and cells. Gene expression analyses for cytokines were conducted in the endometriotic-like cysts and vaginal portion of mice, and immunohistochemistry was performed to evaluate the proliferative activity and localization of macrophages in addition to cytokine expression. The sensation of murine vaginal pain was evaluated using visceromotor responses. RESULTS: NC-2600 reduced the proliferation of the cyst epithelium and vaginal pain sensation. In both cysts and vaginas, P2X4R is mainly expressed in macrophages, and NC-2600 reduces the number of tissue macrophages and reverses the elevated expression of InterleukinL-33 and cyclooxygenase-2 in animals with endometriosis. CONCLUSION: These results indicate unknown pathophysiological roles of P2X4R expressed in local macrophages at the injury site of endometriosis and in the vagina, suggesting the potential therapeutic effects of orally administered P2X4R inhibitors for alleviating the symptoms of endometriosis.