It has been reported that the impaired cytotoxicity of natural killer (NK) cells and abnormal cytokines that are changed by the interaction between ectopic endometrial cells and immune cells is indispensable for the initiation and development of endometriosis (EMS). However, the mechanism of NK cells dysfunction in EMS remains largely unclear. Here, we found that NK cells in peritoneal fluid from women with EMS highly expressed indoleamine 2,3-dioxygenase (IDO). Furthermore, IDO+NK cells possessed lower NKp46 and NKG2D but higher IL-10 than that of IDO-NK. Co-culture with endometrial stromal cells (nESCs) from healthy control or ectopic ESCs (eESCs) from women with EMS led to a significant increase in the IDO level in NK cells from peripheral blood, particularly eESCs, and an anti-TGF-β neutralizing antibody suppressed these effects in vitro. NK cells co-cultured with ESC more preferentially inhibited the viability of nESCs than eESCs did, and pretreating with 1-methyl-tryptophan (1-MT), an IDO inhibitor, reversed the inhibitory effect of NK cells on eESC viability. These data suggest that ESCs induce IDO+NK cells differentiation partly by TGF-β and that IDO further restricts the cytotoxicity of NK cells in response to eESCs, which provides a potential therapeutic strategy for EMS patients, particularly those with a high number of impaired cytotoxic IDO+NK cells.
Xuan-Tong Liu, Hui-Ting Sun, Zhong-Fang Zhang, Ru-Xia Shi, Li-Bing Liu, Jia-Jun Yu, Wen-Jie Zhou, Chun-Jie Gu, Shao-Liang Yang, Yu-Kai Liu, Hui-Li Yang, Feng-Xuan Xu and Ming-Qing Li
Yan Wang, Hualin Huang, Minghua Zeng, Ru-Ping Quan, Jun-Ting Yang, Dan Guo, Ying Sun, Hongwen Deng and Hongmei Xiao
In this study, we investigated a gene-edited (Zp2 MT/MT) rat model of infertility caused by the failure to express the zona pellucida glycoprotein 2 (ZP2) due to the significant reduction of mRNA amount. We examined the defects in the zona pellucida (ZP) caused by ZP2 nullification and the influence of these defects on aspects of oocyte development, including apoptosis and fertilization ability. To investigate the cause of the influence to the oocytes’ development, we evaluated the morphology of follicular transzonal projections (TZPs), known as ‘bridges’, which mediate the bidirectional signaling between the oocyte and surrounding granulosa cells and the level of reactive oxygen species (ROS) in ovulated eggs. Our results showed that two types of ZP defects were generated in the Zp2 MT/MT rat,that is, ZP intact but thinned and ZP cracked (or even absent). The fertilization rate of the ovulated eggs reduced in both types, while increased oocyte apoptosis was observed only in the latter type. Moreover, the increased oocyte apoptosis rate correlated closely with the reduction in follicular TZPs and increased ROS levels in ovulated egg. In conclusion, nullification of rat ZP2 destroyed the integrity of the ZP, impaired the bidirectional signaling between the oocyte and surrounding granulosa cells. Therefore, the resulting infertility likely occurs via elevation of oxidative stress and oocytes apoptosis.