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EP4 regulates glycolysis and dendritic cell maturation in unexplained recurrent miscarriage
Lin Peng1, Chang Liu2, Yao Ye3
1Department of Thyroid and Breast Surgery/School of Clinical Medicine, North Sichuan Medical College/Affiliated Hospital of North Sichuan Medical College, No. 1, South Maoyuan Road, Shunqing District, Nanchong, Sichuan 63700, China.
None:
Unexplained recurrent miscarriage (uRM) is associated with immune dysregulation at the maternal-fetal interface, where dendritic cell (DC) maturation imbalance may play vital roles. This study investigates how prostaglandin E2 receptor EP4 affects DC metabolic reprogramming and maturation, thus regulating immune tolerance in uRM. Immunohistochemistry revealed increased mature DCs (CD86+/CD80+) and decreased immature DCs (CD1a+) in uRM decidua versus healthy controls. Double immunofluorescence demonstrated lower EP4 expression in mature DCs than immature DCs. In vitro, EP4 inhibition promoted monocyte-derived DC maturation (upregulated CD86/CD80) and pro-inflammatory cytokine secretion (TNF-α, IL-6, IL-12), while EP4 activation suppressed these effects. Seahorse analysis showed EP4 blockade enhanced glycolysis via upregulating HK2/PKM2, whereas EP4 activation maintained oxidative metabolism. Mechanistically, EP4 knockdown in DCs suppressed PI3K-AKT-mTOR signaling. These findings suggest that EP4 may be involved in DC maturation through modulation of glycolytic metabolism and PI3K-AKT-mTOR signaling in uRM, while EP4 agonism preserves DC immaturity and metabolic quiescence, suggesting EP4 as a potential therapeutic target for restoring maternal-fetal immune homeostasis in uRM.
