Estrogen receptor upregulates CCL2 via NF-B signaling in endometriotic stromal cells and recruits macrophages to promote the pathogenesis of endometriosis
Estrogen receptor upregulates CCL2 via NF-B signaling in endometriotic stromal cells and recruits macrophages to promote the pathogenesis of endometriosis
复制标题
雌激素受体β通过子宫内膜异位症基质细胞中的NF-kappaB信号传导上调CCL2，并招募巨噬细胞促进子宫内膜异位症的发病机制。
DOI：
10.1093/humrep/dez019
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发表时间：
2019-04-01
影响因子：
6.1
通讯作者：
Zhang, Zongfeng
中科院分区：
文献类型：
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作者：
Gou, Yanling;Li, Xue;Zhang, Zongfeng
研究问题：子宫内膜异位症基质细胞（ESCs）中雌激素受体（ER）的激活如何参与巨噬细胞的募集，从而促进子宫内膜异位症的发病？综述答案ESCs通过活化B细胞核因子κ轻链增强子（NF-B）信号调节C-C基序趋化因子配体2（CCL 2）的产生，从而招募巨噬细胞到异位病灶以促进发病。最近的研究表明，ER通过调节细胞凋亡和炎症反应在子宫内膜异位症的发展中起重要作用。研究设计、规模、持续时间（子宫内膜异位症妇女，经腹腔镜检查和组织学分析诊断）和14名对照对象/材料：地点：方法对22例卵巢恶性肿瘤和深度浸润型子宫内膜异位症患者的组织和间质细胞进行分离，并与14例正常周期患者的组织和间质细胞进行比较免疫组化、定量PCR、Western blot、细胞迁移试验和克隆形成试验。P值< 0.05被认为是显著的，并且在至少三种不同的细胞制备物中重复实验。主要结果和机会的作用我们观察到，累积的巨噬细胞被募集到异位环境中，并且主要采用交替激活的巨噬细胞（M2）表型。为了揭示其潜在机制，我们进行了一系列实验，发现ER的高表达通过NF-B信号传导导致CCL 2的产生，并且巨噬细胞被募集到异位环境。体外共培养实验也表明，募集的巨噬细胞反过来可以促进ESCs的增殖和克隆形成能力。总的来说，ESCs中ER的激活通过NF-B/CCL 2信号参与巨噬细胞募集，随后似乎促进了子宫内膜异位症的发病机制。我们确定了在我们研究中使用的样本中M2巨噬细胞的主要存在，但是募集的巨噬细胞如何获得M2表型的潜在机制尚不明确。本研究由国家自然科学基金（81671430）资助。作者没有利益冲突。
STUDY QUESTION How is the activation of estrogen receptor (ER) in endometriotic stromal cells (ESCs) involved in macrophage recruitment to promote the pathogenesis of endometriosis?SUMMARY ANSWER ER modulates the production of C-C motif chemokine ligand 2 (CCL2) via nuclear factor kappa-light-chain-enhancer of activated B cells (NF-B) signaling in ESCs and thus recruits macrophages to ectopic lesions to promote pathogenesis.WHAT IS KNOWN ALREADY Macrophages are mainly recruited to the peritoneal cavity to promote the pathogenesis of endometriosis. Recent studies have demonstrated that ER plays an important role in the progression of endometriosis through modulating apoptosis and inflammation.STUDY DESIGN, SIZE, DURATION An observational study consisting of 22 cases (women with endometriosis, diagnosed by laparoscopy and histological analysis) and 14 controls (without endometriosis) was carried out.PARTICIPANTS/MATERIALS, SETTING, METHODS Tissues and stromal cells that were isolated from 22 patients with ovarian endometrioma and deeply infiltrating endometriosis were compared with tissues and stromal cells from 14 patients with normal cycling endometrium using immunohistochemistry, quantitative PCR, Western blot, cell migration assay and cloning formation assay. P values < 0.05 were considered significant, and experiments were repeated in at least three different cell preparations.MAIN RESULTS AND THE ROLE OF CHANCE We observed that accumulated macrophages were recruited to the ectopic milieu and mainly adopted an alternatively activated macrophage (M2) phenotype. To reveal the underlying mechanism for this, we conducted a series of experiments and found that high expression of ER led to the production of CCL2 via NF-B signaling and macrophages were recruited to the ectopic milieu. An in vitro co-culture assay also suggested that the recruited macrophages in turn could promote the proliferation and clonogenic ability of ESCs. Overall, the activation of ER in ESCs is involved in macrophage recruitment via NF-B/CCL2 signaling and subsequently appears to promote the pathogenesis of endometriosis.LARGE SCALE DATA N/A.LIMITATIONS, REASONS FOR CAUTION Due to the limitations of obtaining surgical specimens, endometrioma tissues were collected mainly from women diagnosed with middle to late stage endometriosis. We identified thepredominant presence of M2 macrophages in the samples used in our study, but the underlying mechanism of how recruited macrophages acquire the M2 phenotype is undefined.WIDER IMPLICATIONS OF THE FINDINGS This work provides novel insight into the mechanism by which ER may modulate macrophage infiltration and promote pathogenesis, which may provide a new therapeutic target for endometriosis.STUDY FUNDING/COMPETING INTEREST(S) This study was supported by the National Natural Science Foundation of China (81671430). The authors have no conflicts of interest.