子宫内膜异位症的新机制：ESC内ERβ/twist1通路介导的旁分泌途径募集活化M2型巨噬细胞

M2 macrophages in the microenvironment of endometriotic foci inhibit inflammatory response and balance Th1 type immunity, and are crucial in the formation of endometriosis by promoting the proliferation, invasion and angiogenesis of endometrial stromal cells (ESC). However, the relationship between M2 macrophages and estrogen receptor β (ERβ) is not clear. Our previous studies have shown that the expressions of ERβ, Twist1 and CD163 are positively correlated in the endometriotic foci, and in ESC stimulation or inhibition of ERβ can increase or reduce the expressions of MCP-1 and Twist1, and silence of Twist1 reduces the expression of MCP-1. Thus, we speculate that ERβ/twist1 pathway-mediating-paracrine of ESC is able to recruit and alternatively activate macrophages, which participates in the formation of endometriosis. To test this hypothesis, we will employ macrophage migration assay, ESC-macrophage co-culture system, mice model of endometriosis, and the interventions of the signal pathways with various pharmacological agents and siRNA to observe the recruitment, activation and secretion of macrophages and the effects of M2 macrophages on the biological function of ESC on the basis of our previous data. This study will for the first time elucidate the novel mechanisms that ERβ/twist1 pathway mediated recruitment and alternative activation of macrophages in the microenvironment of endometriotic foci to participate in endometriosis formation and immune escape, and will be expected to provide new ideas and targets for the intervention of endometriosis.

子宫内膜异位症（EM）微环境中M2型巨噬细胞（MΦ）抑制炎症反应和平衡Th1型免疫，促进内膜间质细胞（ESC）增殖、侵袭及血管生成，是EM形成的关键细胞，然而，其与ERβ关系尚不清楚。我们前期研究发现：EM病灶内ERβ、twist1和CD163表达呈正相关，ESC内激动或阻断ERβ可增加或减少twist1和MCP-1表达，沉默twist1可抑制MCP-1表达。因此，我们假设：ESC内ERβ/twist1通路介导旁分泌途径募集活化M2型MΦ并参与EM病灶形成。本项目拟在已有研究基础上，建立MΦ迁移模型、ESC-MΦ共培养体系和小鼠EM模型，使用药物、siRNA等阻断假说中调控通路，通过观察MΦ募集、活化和分泌情况以及M2型MΦ对ESC生物学功能的影响来证实本假说。本项目首次解析ERβ通过调控EM免疫微环境中MΦ募集活化来参与EM病灶形成和免疫逃逸的新机制，预期将为EM干预提供新思路和新靶点。

近年来子宫内膜异位症（EMs）的发病率呈上升趋势，约有10%-15%的育龄期妇女受其困扰。目前EMs的发生机制尚未完全阐明，存在诸多学说，如经血逆流种植学说、在位内膜决定论、免疫逃逸学说等，但迄今为止尚没有任何一种学说能够明确诠释EMs的发生机制。EMs微环境中M2型巨噬细胞具有抑制炎症反应和平衡Th1型免疫的作用，其可促进内膜间质细胞（ESCs）增殖、侵袭及血管生成，是EMs形成的关键细胞。此外，EMs作为一种雌激素依赖性疾病，雌激素受体β（ERβ）已被证实可促进ESCs增殖、侵袭和迁移等，是EMs发生发展的关键分子。然而，探究ERβ是否通过调控EMs微环境中巨噬细胞而参与异位灶形成和免疫逃逸的研究尚未见报道。本项目通过半定量免疫组化、巨噬细胞迁移模型建立、ESCs-巨噬细胞共培养体系、细胞因子蛋白芯片检测、慢病毒转染敲除ERβ和小鼠EMs模型等实验方法，从临床组织样本、体外细胞实验和体内动物模型三个层面进行研究，结果发现EMs病灶中ESCs高表达ERβ，ERβ通过转录激活NF-κB信号通路促进单核细胞趋化蛋白-1（MCP-1，又称CCL2）表达，募集巨噬细胞到EMs局部病灶，进而促进ESCs增殖和克隆形成，参与EMs的发生发展过程。本项目以ERβ通过NF-κB信号通路调控CCL2为切入点，深入解析了ERβ通过调控EMs病灶微环境中巨噬细胞的募集和M2型极化来参与异位灶形成和免疫逃逸的新机制，为EMs的研究开辟了ERβ与EMs免疫调节网络相结合的新方向，最终可能为EMs干预提供新思路和新靶点。

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