转录因子EB通过调控NLRP3/IL-1β炎症通路抑制子宫内膜异位症炎症反应的分子机制研究

Endometriosis (Ems) causes clinical symptoms such as infertility, dysmenorrhea, and chronic pelvic pain in women of childbearing age and its exact cause is not clear. The incidence of Ems in female populations in China is about 10%. Ems can be considered as a persistent chronic inflammatory response of the endometrium. Studies have shown that TFEB has anti-inflammatory function in a variety types of cells. Our previous work also confirmed that TFEB has obvious anti-inflammatory function in various types of cells including endometrial cells, and TFEB can significantly inhibit the expression of IL-1β and other inflammatory factors, which suggesting that TFEB has anti-inflammatory properties in different kinds of cells. In addition, the NLRP3/IL-1β inflammatory signal axis plays an important role in the inflammation of Ems, while the NLRP3/IL-1β inflammatory signal axis in tumor-associated macrophages (TAMs) of breast cancer can be inhibited by TFEB in TAMs, resulting in tumor growth retardation..Therefore, we hypothesized that in the pathology model of Ems, TFEB inhibits the NLRP3/IL-1β signal axis to resist the inflammatory response of endometrial cells, thereby blocking endometrial cell adhesion and growth in endometriosis. Over-expression or knocking down TFEB by drugs or viruses will be conducted in Ems animals model which induced by transplanting with endometrial cells or tissues. Combining with cell biology and molecular biology tools, our experiment unveils the molecular mechanism of NLRP3/IL-1β signaling axis suppression by TFEB in endometrial cells. Our work will provide a new theoretical basis and experimental basis for the effective prevention and treatment of clinical Ems and therapeutic target mining.

子宫内膜异位症(Ems)引起育龄女性不孕、痛经等临床症状，确切发病机理尚不明确。我国女性人群中Ems发病率约为10%。Ems是持续性慢性炎症疾病。我们前期的实验数据表明TFEB在包括子宫内膜细胞(ECs)在内的多种细胞中具有抗炎功能，能显著抑制IL-1β等多个炎症因子的表达。此外，NLRP3/IL-1β炎症信号轴在Ems的内膜炎症中起着重要的作用，而该信号轴在乳腺癌中能被肿瘤相关的巨噬细胞中的TFEB抑制而导致肿瘤的生长阻滞。因此，我们提出假设:在Ems病理模型中TFEB 抑制NLRP3/IL-1β信号轴来抵抗ECs的炎症反应，进而阻滞子宫内膜异位病灶细胞的黏附和生长。本实验在移植诱导的Ems模型动物中过表达或敲低TFEB，结合细胞生物学，分子生物学揭示TFEB抑制NLRP3/IL-1β信号轴进而抵抗ECs炎症的分子机制，为临床Ems的治疗靶点挖掘提供新理论依据和实验基础。

背景：子宫内膜异位症(Ems)引起育龄女性不孕、痛经等临床症状，在我国女性中的发病率约为10%。Ems被认为是一种慢性炎症疾病，是妇科中的疑难病，其确切病因尚不明确。多项研究表明TFEB在多种细胞中具有抗炎功能。.方法：本研究通过分子，细胞生物学以及生物化学等技术方法，利用体外细胞、病人组织探讨TFEB在子宫内膜异位症中的内膜上皮细胞的抗炎保护作用，以及这种保护作用所涉及的分子信号调控通路。.结果：我们发现TFEB在EMs疾病组的子宫内膜组织中的表达明显低于健康对照组（蛋白和mRNA结果），而炎症信号相关基因IL-1β，TNF-α，MMP9和 IL8在EMs疾病组子宫内膜组织中的表达却刚好相反，表达量高于健康对照组。TFEB在人子宫内膜上皮细胞中过表达可抑制 TNF-α引起的内膜上皮细胞的炎症基因表达的上调。相反，在人子宫内膜上皮细胞敲低TFEB的表达则引起细胞的炎症反应，炎症因子NFKB1，NLRP3，IL-1 β的 mRNA 的表达明显上调。.结论：因此，我们的结果初步提示TFEB 可以抑制宫内膜组织中内膜上皮的炎症反应，进而缓解Ems的炎症症状。TFEB在子宫内膜上皮细胞中的炎症抑制作用可能是通过NLRP3/IL-1β信号轴来实现。本实验下一步将在移植诱导的Ems模型动物中过表达或敲低TFEB，进一步探讨TFEB抑制NLRP3/IL-1β信号轴进而抵抗子宫内膜炎症的分子机制，为临床Ems的有效防治以及治疗靶点挖掘提供新理论依据和实验基础。