PrPC Promotes Endometriosis Progression by Reprogramming Cholesterol Metabolism and Estrogen Biosynthesis of Endometrial Stromal Cells through PPARα Pathway.

Endometriosis (EMs) is characterized as an estrogen-dependent disease. Whereas, the underlying mechanism for activated estrogen biosynthesis in EMs lesions is largely unknown. We analyzed cholesterol metabolism and estrogen biosynthesis condition of EMs lesions by biological information analysis of GEO datasets, and further verified both in vitro and in vivo by constructing EMs models with uterus fragments from donors of PRNP knockout mouse (Prnp-/-, KO119), Octapeptide repeat region of PRNP knockout mouse (KO120) and PRNP transgenic mouse (Tg20). We found that transcriptome of cholesterol metabolism and estrogen-converting enzymes were disturbed in EMs patients, and cellular cholesterol concentration and local estradiol level were substantially increased in EMs lesions, as well as the high level of prion (PrPC, encoded by PRNP). Notably, 17-ß estradiol stimulation significantly up-regulated PrPC expression in endometrial stromal cells (ESC) and PrPC promoted the proliferative, migratory and invasive abilities of ESC, and was further verified to accelerate EMs progression in mouse models. More importantly, PrPC promoted cholesterol accumulation and activated estrogen biosynthesis of ESC in a PPARα pathway-dependent manner. Taken together, this study suggests that PrPC-cholesterol metabolism/estrogen biosynthesis contributes to the progression of EMs by negatively regulating PPARα pathway, and could be potential therapeutic targets for EMs intervention.

Estrogen-regulated CD200 inhibits macrophage phagocytosis in endometriosis.

OBJECTIVES: Endometriosis (EMS) is a benign disease that is related to estrogen, immune disorders and inflammation. The purpose of this research was to determine the expression of CD200 in EMS and to clarify its role in the pathogenesis of the disease. METHODS: The levels of serum CD200 in patients with and without EMS were determined by ELISA. Furthermore, the expression of CD200 in normal eutopic endometrium and ectopic endometrium was detected by immunohistochemistry and western blotting. The CD200 receptor (CD200R) in macrophages in peritoneal fluid (pMØ) obtained from controls and patients with EMS was examined by western blotting. CD200 expression in human endometrial stromal cells (HESCs) stimulated with 17ß-estradiol (E2) was measured by western blotting. Furthermore, macrophages were stimulated with different concentrations of CD200 and the effect on phagocytosis was analyzed. RESULTS: The plasma CD200 levels of patients with EMS was significantly increased compared with controls (P = 0.0173, 95%CI [18.75, 159.6]). Compared with normal eutopic endometrium, the expression of CD200 was significantly increased in ectopic endometrial tissues. The CD200R expression in pMØ obtained from patients with EMS was increased compared with the controls (P = 0.0244). CD200 expression in HESCs stimulated with E2 was up-regulated. As the levels of CD200 increased, macrophage phagocytosis in vitro gradually decreased. CONCLUSIONS: CD200 is an estrogen-induced molecule that impairs macrophage phagocytosis and may contribute to the immune escape of ectopic lesions in EMS.