Decreased Expression of EZH2 in Granulosa Cells Contributes to Endometriosis-Associated Infertility by Targeting IL-1R2.
Decreased Expression of EZH2 in Granulosa Cells Contributes to Endometriosis-Associated Infertility by Targeting IL-1R2.
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颗粒细胞中 EZH2 表达减少通过靶向 IL-1R2 导致子宫内膜异位症相关不孕
DOI：
10.1210/endocr/bqac210
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发表时间：
2022-12-19
期刊：
影响因子：
4.8
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中科院分区：
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子宫内膜异位症是一种以慢性盆腔疼痛和不孕为特征的常见妇科疾病，其导致不孕的机制仍然不清楚。黄素化未破裂卵泡综合征是最常见的排卵功能障碍类型，是卵泡发育相关性不孕症的一个原因，涉及获得的成熟卵母细胞数量减少。排卵由卵泡微环境中产生的促黄体生成激素和旁分泌信号控制。通常，白细胞介素（IL）-1β在子宫内膜异位症卵泡液中升高，从而通过激活细胞外调节激酶1/2和CCAAT/增强子结合蛋白β途径放大排卵信号。然而，IL-1β的这种促排卵作用并不发生在子宫内膜异位症患者中。为了阐明子宫内膜异位症排卵功能障碍的机制，我们分析了氧化应激和IL-1β表达对子宫内膜异位症卵泡的影响。我们发现，氧化应激降低EZH 2的表达和降低H3 K27 Me 3水平子宫内膜异位症卵巢颗粒细胞（GC）。小鼠卵巢GCs中选择性Ezh 2耗竭通过干扰卵丘-卵母细胞复合体扩增和减少表皮生长因子样因子表达来降低生育力。GC的基因表达和H3 K27 Me 3 ChIP测序（ChIP-Seq）揭示了IL-1受体2（IL-1 R2），一种在排卵期间抑制IL-1β介导的炎症级联反应的高亲和力IL-1β受体，是EZH 2-H3 K27 Me 3轴的关键靶基因。此外，IL-1β的加入不能恢复Ezh 2敲低后的排卵，表明IL-1 R2在子宫内膜异位症中的重要功能。因此，我们的研究结果表明，减少GC中的EZH 2和H3 K27 Me 3通过增加IL-1 R2表达来抑制排卵信号，这可能最终导致糖尿病相关的不孕症。
The mechanism by which endometriosis, a common gynecological disease characterized by chronic pelvic pain and infertility, causes infertility remains elusive. Luteinized unruptured follicle syndrome, the most common type of ovulatory dysfunction, is a cause of endometriosis-associated infertility involving reduced numbers of retrieved and mature oocytes. Ovulation is controlled by luteinizing hormone and paracrine signals produced within the follicle microenvironment. Generally, interleukin (IL)-1β is elevated in endometriosis follicular fluid, whereby it amplifies ovulation signals by activating extracellular-regulated kinase 1/2 and CCAAT/enhancer binding protein β pathways. However, this amplification of ovulation by IL-1β does not occur in patients with endometriosis. To illuminate the mechanism of ovulatory dysfunction in endometriosis, we analyzed the effect of oxidative stress and IL-1β expression on endometriosis follicles. We found that oxidative stress decreased EZH2 expression and reduced H3K27Me3 levels in endometriosis ovarian granulosa cells (GCs). Selective Ezh2 depletion in mice ovarian GCs reduced fertility by disturbing cumulus-oocyte complex expansion and reducing epidermal growth factor-like factor expression. Gene expression and H3K27Me3 ChIP-sequencing (ChIP-Seq) of GCs revealed IL-1 receptor 2 (IL-1R2), a high-affinity IL-1β-receptor that suppresses IL-1β-mediated inflammatory cascades during ovulation, as a crucial target gene of the EZH2-H3K27Me3 axis. Moreover, IL-1β addition did not restore ovulation upon Ezh2 knockdown, indicating a vital function of IL-1R2 in endometriosis. Thus, our findings show that reducing EZH2 and H3K27Me3 in GCs suppressed ovulatory signals by increasing IL-1R2 expression, which may ultimately contribute to endometriosis-associated infertility.