基于IL-33/ST2L通路调控异位灶微环境M2型巨噬细胞极化探讨补肾活血法治疗子宫内膜异位症的作用机制

Endometriosis (EMs) is a common disease in women of childbearing age. Although it is a benign disease, it has the malignant biological behaviors such as infiltration, metastasis and recurrence. Modern medicine lacks effective methods to control the disease and prevent recurrence. According to Chinese medicine, "deficiency of kidney and blood stasis" is the basic pathogenesis of EMs, invigorating kidney and activating blood is basic method to treat. The team found in previous studies, the method of invigorating kidney and activating blood could inhibit the growth of ectopic lesions and adjust immune factors. M2 macrophage polarization and IL-33 /ST2L pathway are closely related to immune suppression. A number of independent studies have found that the pathogenesis of EMs is related to IL-33 /ST2L pathway and M2 macrophage polarization, but there is no in-depth study on how traditional Chinese medicine prescriptions affect the polarization of M2 macrophages through IL-33 /ST2L pathway in EMs. Therefore, based on the previous research work, this project intends to discuss the effect of invigorating kidney and activating blood method on M2 macrophages and IL-33 /ST2L pathway in EMs model mice, and then explore the target of this therapy, and finally reveal the mechanism of this therapy in treating EMs from the perspective of molecular cellular immunology.

子宫内膜异位症(EMs)是育龄妇女的多发病、常见病，虽为良性疾病，但有浸润、转移及复发等恶性生物学行为，被成为“良性癌”。现代医学缺乏有效的控制病情及预防复发的方法。中医学认为“肾虚不足、瘀血内结” 是EMs的基本病机，据此病机而立的补肾活血法是治疗EMs的基本大法。项目组在前期研究中发现补肾活血法有抑制异位病灶生长，调节免疫因子的作用。M2型巨噬细胞极化及IL-33/ST2L通路与免疫抑制密切相关。多项独立的研究发现EMs的发病与IL-33/ST2L通路、M2型巨噬细胞极化相关，但关于中药方剂如何在EMs中通过IL-33/ST2L通路影响M2型巨噬细胞极化未见深入研究。因此，本项目在前期研究工作基础上，探讨补肾活血法对EMs模型鼠M2型巨噬细胞及IL-33/ST2L通路的影响，进而探寻该治法的作用靶点，最终从分子细胞免疫学的角度揭示该治法治疗EMs的的作用机制。

补肾活血法是治疗子宫内膜异位症的重要原则。EMs患者免疫细胞失能，炎性介质异常分泌造成微环境的免疫缺陷，是EMs的发病关键。本研究通过离体、在体、阻断实验，借助实时定量PCR、western blot、流式细胞术等技术，证实了EMs背景下活化的IL-33/ST2L通路，诱导异位灶微环境维持巨噬细胞M2表型，促进异位病灶的种植生长。同时，本研究还发现补肾活血法指导下的中药复方可抑制IL-33/ST2L通路的激活，减少MyD88、TRAF6、NF-κB等下游关键蛋白的表达，从而抑制巨噬细胞的M2表型，调节EMs免疫微环境，抑制子宫内膜异位症的进展。本研究明确了IL-33/ST2L对子宫内膜异位症巨噬细胞极化及免疫微环境的调控作用，及基于该机制下补肾活血法复方干预子宫内膜异位症的具体环节。本课题有利开发子宫内膜异位症治疗新靶点，诠释补肾活血法治疗EMs的科学性，为中医药治疗EMs提供了新思路。