1-Methyl-tryptophan attenuates regulatory T cells differentiation due to the inhibition of estrogen-IDO1-MRC2 axis in endometriosis.
1-Methyl-tryptophan attenuates regulatory T cells differentiation due to the inhibition of estrogen-IDO1-MRC2 axis in endometriosis.
复制标题
1-甲基色氨酸因抑制子宫内膜异位症中雌激素-IDO1-MRC2轴而减弱调节性 T 细胞分化
DOI：
10.1038/cddis.2016.375
复制
发表时间：
2016-12-01
影响因子：
9
通讯作者：
Zhu X
中科院分区：
文献类型：
--
作者：
Wei C;Mei J;Tang L;Liu Y;Li D;Li M;Zhu X
Foxp3+ regulatory T (T reg) cells contribute to the local dysfunctional immune environment in endometriosis, an estrogen-dependent gynecological disease, which affects the function of ectopic endometrial tissue clearance by the immune system. The reason for the high percentage of peritoneal T reg in endometriosis patients is unknown. Here, we show that the proportion of peritoneal T reg cells increases as endometriosis progresses. To determine the probable mechanism, we established a naive T cell-macrophage-endometrial stromal cell (ESC) co-culture system to mimic the peritoneal cavity microenvironment. After adding 1-methyl-tryptophan (1-MT), a specific inhibitor of indoleamine 2, 3-dioxygenase-1 (IDO1), to the co-culture system, we found that the differentiation of T reg cells, mainly IL-10+ T reg cells, decreased. Therefore, 1-MT-pretreated ESCs-educated T reg cells performed impaired suppressive function. Moreover, estrogen promoted the differentiation of T reg cells by elevating IDO1 expression in the ectopic lesion. Subsequently, we examined mannose receptor C, type 2 (MRC2), which is an up-stream molecule of IL-10, by bioinformatics analysis and real-time PCR validation. MRC2 expression in ectopic ESCs was notably lower than that in normal ESCs, which further negatively regulated the expression of IDO1 and Ki-67 in ESCs. Furthermore, MRC2 is required for T reg differentiation in the ectopic lesion, especially that for CD4 high T reg. Therefore, MRC2-silenced ESCs-educated T reg manifested a stronger suppressive function in vitro. Consistently, the percentage of T reg increased when MRC2-shRNA was administered in the peritoneal cavity of endometriosis-disease mice model. Besides, 1-MT improved the condition of endometriosis, in terms of reducing the number and weight of total ectopic lesions in vivo. These results indicate that the estrogen-IDO1-MRC2 axis participates in the differentiation and function of T reg and is involved in the development of endometriosis. Thus, blockage of IDO1 in the ectopic lesion, which does not influence physiological functions of estrogen, may be considered a potential therapy for endometriosis.
