子宫内膜异位症中IL-37调节Th17/Treg细胞免疫平衡对子宫内膜容受性的作用机制研究

Endometriosis (EMs) is a disease that occurs in menstruating females and is characterized by such symptoms as pelvic pain, dysmenorrhea, and infertility. Our current understanding of the mechanism of EMs related infertility is not yet clear. Our previous study found that the increase of proinflammatory cytokines in peripheral blood of EMs resulted in the imbalance of Th17 / Treg in eutopic endometrium. In addition, the expression of IL-37, which is an inflammatory cytokine, was downregulated in eutopic endometrium in EMs group than in normal control group. Whereas, IL-6 (an important factor in Th17 cell differentiation) and downstream transcription factor levels increased. It is speculated that IL-37 secretion is too small to inhibit IL-6-mediated Th17 cell differentiation, leading to increased endometrial Th17 and immune balance disorders. It still make the gene expression of endometrial receptivity disorders, which may be one of an important pathogenesis of EMs related infertility. In order to support this hypothesis, this study sought to investigate the relationship between IL-37 expression and Th17 / Treg differentiation in human endometrium and pregnancy outcome. IL-37 is shown to affect Th17 differentiation through the above pathways through cellular and animal experiments, and endometrial receptivity and embryo implantation. This project will give a new perspective to elucidate the immunological mechanisms that cause EMs related infertility and is expected to provide new theories and ideas for the prevention and treatment of EMs related infertility.

子宫内膜异位症（EMs）是育龄妇女常见疾病，与女性不孕密切相关，其机制目前尚不清楚。我们前期研究发现EMs外周血中促炎性细胞因子增多，导致子宫内膜组织Th17/Treg平衡向Th17偏移；同时发现在位内膜中抑炎因子IL-37表达下调，而炎性因子IL-6（Th17细胞分化的重要因子）及下游转录因子水平增高。我们推测子宫内膜组织中IL-37表达下降，不足以抑制IL-6介导的Th17细胞分化，导致Th17增多，进而使得容受性相关基因表达紊乱，可能是EMs相关不孕的重要发病机制。为证实这一推论，本项目拟研究：人子宫内膜中IL-37及受体的表达和Th17/Treg分化及表达与妊娠结局的关系；通过细胞和动物实验证实IL-37通过IL-6-STAT3-RORγt影响Th17分化，及内膜容受性和胚胎着床。本项目将从一个新的角度，阐明引起EMs不孕的免疫学机制，有望对EMs不孕的防治提供新理论和新思路。

子宫内膜异位症（EMs）患者的腹腔内免疫相关细胞功能的改变和细胞因子含量的变化（包括IL-6、IL-8、IL-10、IL-1β、IL-17A、IFN-γ和TNF-α等）可能诱导建立不利于妊娠的子宫免疫环境。在小鼠自然流产模型和复发性流产患者蜕膜或流产物组织中均可观察到Th17细胞比例增高，分泌的IL-17浓度增高，Treg细胞比例下降。然而，EMs造成不孕的具体影响机制至今尚未阐明。本项目研究中，将着重探讨抑制因子IL-37调控Th17细胞分化，导致 Th17/Treg免疫失衡，影响子宫内膜容受性和胚胎着床的作用。我们在研究中发现，EMs在位内膜组织中IL-37的低表达和IL-6的高表达可以导致Th17/Treg细胞比例失衡。EMs患者或EMs假孕鼠子宫内膜组织中与Th17、Treg细胞分化相关的信号分子的基因表达异常（如IL-6、IL-17、ROR-γt mRNA表达增高，而TGF-β、Foxp3 mRNA表达降低）导致子宫内膜容受性相关基因β3、LIF和HOXA10的mRNA的表达水平下调。IL-37能降低子宫内膜细胞中IL-6和IL-17mRNA的表达。体内注射IL-17A导致EMs假孕鼠受孕率下降，着床胚泡数减少，外源性IL-37增加EMs孕鼠着床胚泡数。完成本项目研究内容的基础上，我们根据研究的新发现扩展了相关研究内容。主要研究结果包括：（1）在子宫内膜异位病变存在的腹腔炎性环境中，IL-37通过Akt和Erk1/2信号通路调节子宫内膜增殖、侵袭、血管生成和炎症，改善腹腔环境，抑制子宫内膜病变的生长。（2）IL-6是子宫内膜异位症疾病和不孕中发挥作用的关键因子。IL-6协同G-CSF通过STAT3通路调节中性粒细胞，改变中性粒细胞中血管生成相关基因Mmp9、Bv8和Trail mRNA和蛋白质的表达水平，促进早期子宫内膜异位症的建立。.本项目研究从IL-6-STAT3-RORγt-IL17轴对EMs患者子宫内膜容受性的影响的角度阐明了IL-37调整Th17/Treg细胞免疫平衡，提高受孕率和胚泡着床率的作用，为探索提高种植率干预新靶点提供了理论基础。同时阐明了炎性因子G-CSF和IL-6协同改变中性粒细胞功能，促进异位病灶的形成；IL-37具有抑制子宫内膜异位病灶生长的作用。本研究为EMs引起的不孕的防治提供理论依据。