转录因子EB（TFEB）参与母胎界面免疫调节的作用机制研究

The maternal–fetal interface is an immunologically unique site that allows the tolerance to the allogenic fetus and maintains host defense against possible pathogens. Balanced immune responses are required for the maintenance of successful pregnancy. Interestingly, the composition of these immune cells and Immunol cytokines is highly specialized and distinct from non-uterine organs. Based on which, establishes the fetal-maternal tolerance and plays a significant role in the process of embryo implantation, decidualization, as well as vascular remodeling. In our previous study on the differential gene expression in peripheral blood linked to human pregnancy outcome after IVF-ET showed that inflammation related factors, such as HLA-A and IL-1β, were potentially associated with pregnancy failure. Meanwhile, in our previous study on the differential proteome in the endometrium from obesity mice also showed that proteins related to infection, inflammation and immune response were highly expressed in endometrium from obesity mice which might link to the poor pregnancy in obese female. Notably, transcription factor EB (TFEB) was increased expression in obese endometrium and its expression was closed related to the process of pregnancy, which attracts our attention. Interestingly, it has reported that TFEB is the master transcriptional regulator of autophagy and lysosome biogenesis and recent advances have linked TFEB to the regulation of the immune response through the endolysosmal pathway and by direct transcriptional activation of immune related genes. Therefore, this applying project is focus on the mechanism of TFEB expressed in endometrium effects on the immune modulation at maternal–fetal interface during early pregnancy and will further improve the function of TFEB in regulation of the immune response through the endolysosmal pathway and by direct transcriptional activation of immune related genes thus is further crucial for the maintenance of successful pregnancy. Moreover, the correlation between TFEB and successful pregnancy in clinical assisted reproduction will be investigated to elucidate the pathogenesis of some certain kinds of pregnancy failure.

母胎界面的免疫调节是成功妊娠的关键因素。与外周免疫调节不同，母胎界面免疫调节涉及一系列特殊的免疫细胞和免疫调节因子，它们维持了母胎免疫耐受，还参与了早期妊娠过程中胚泡植入、蜕膜化、血管重塑等重要生物学活动。前期研究中，我们比较了不同妊娠结局的IVF助孕患者外周血表达谱差异，并利用肥胖小鼠模型和蛋白组学分析，发现母体免疫状态可以影响妊娠结局。我们注意到，在肥胖小鼠子宫内膜中转录因子TFEB表达显著上升，且其表达水平与妊娠进程密切相关。有研究报道，TFEB调节了免疫细胞分化，参与了炎症反应和免疫应答过程。因此，本课题将探索子宫内膜/蜕膜中TFEB对妊娠的影响及分子机制，明确TFEB可调控免疫相关基因转录和溶酶体系统活性，调节免疫细胞分化和免疫应答，进而影响母胎界面免疫调节。同时，通过临床研究，探索TFEB表达与妊娠结局的相关性，阐明由其引起的子宫内膜免疫异常，最终导致妊娠失败的病理机制。

母胎界面的免疫调节是成功妊娠的关键因素。与外周免疫调节不同，母胎界面免疫调节涉及一系列特殊的免疫细胞和免疫调节因子，它们维持了母胎免疫耐受，还参与了早期妊娠过程中胚泡植入、蜕膜化、血管重塑等重要生物学活动。本课题研究中，我们成功构建了子宫内膜基质细胞和上皮细胞特异的Tfeb条件性基因敲除小鼠，并确认该小鼠具有雌性生育力下降的表型。同时，通过组织学和细胞学分析，我们确认子宫内膜基质细胞中TFEB缺失通过影响细胞清除功能造成局部炎症状态，进而导致子宫内膜局部巨噬细胞数量增加、M1极化。这种巨噬细胞失调可影响早期妊娠，最终影响雌性生育力。通过本课题研究，我们提出一个观点：子宫内膜存在炎症性衰老现象。这是影响子宫内膜免疫状态及妊娠失败的致病机制之一，也为临床不孕、复发性流产等问题的预防和治疗提供新的思路。