Estradiol Is a Critical Mediator of Macrophage-Nerve Cross Talk in Peritoneal Endometriosis
Estradiol Is a Critical Mediator of Macrophage-Nerve Cross Talk in Peritoneal Endometriosis
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DOI：
10.1016/j.ajpath.2015.04.012
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发表时间：
2015-08-01
影响因子：
6
通讯作者：
Saunders, Philippa T. K.
中科院分区：
文献类型：
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作者：
Greaves, Erin;Ternp, Julia;Saunders, Philippa T. K.
子宫内膜异位症发生在大约10%的妇女，并与持续的盆腔疼痛。其定义为子宫外存在子宫内膜组织（病变），最常见于腹膜上。周围神经炎症是一个以神经纤维和巨噬细胞浸润到病变中为特征的过程，在神经纤维变性相关疼痛中起着关键作用。我们的目的是确定雌二醇（E2）在调节腹腔子宫内膜异位症巨噬细胞和神经之间的相互作用中的作用。通过使用人体组织和子宫内膜异位症小鼠模型，我们证明了从妇女和小鼠中恢复的病变中的巨噬细胞对雌激素受体β呈免疫阳性，高达20%为雌激素受体α阳性。在小鼠中，E2治疗增加了病变中巨噬细胞的数量以及Csf 1，Nt 3和酪氨酸激酶神经营养因子受体TrkB编码的mRNA的浓度。通过使用体外模型，我们确定了E2处理大鼠背根神经节神经元增加了趋化因子C-C基序配体2的mRNA浓度，该趋化因子C-C基序配体2刺激集落刺激因子1分化的巨噬细胞的迁移。相反，E2与集落刺激因子1巨噬细胞的孵育增加了脑源性神经营养因子和神经营养因子3的浓度，这刺激了神经节外植体的神经突生长。总之，我们证明了E2在刺激巨噬细胞-神经相互作用中的关键作用，为子宫内膜异位症是一种雌激素依赖性神经炎性疾病提供了新的证据。
Endometriosis occurs in approximately 10% of women and is associated with persistent pelvic pain. It is defined by the presence of endometrial tissue (lesions) outside the uterus, most commonly on the peritoneum. Peripheral neuroinflammation, a process characterized by the infiltration of nerve fibers and macrophages into lesions, plays a pivotal role in endometriosis-associated pain. Our objective was to determine the role of estradiol (E2) in regulating the interaction between macrophages and nerves in peritoneal endometriosis. By using human tissues and a mouse model of endometriosis, we demonstrate that macrophages in lesions recovered from women and mice are immunopositive for estrogen receptor beta, with up to 20% being estrogen receptor alpha positive. In mice, treatment with E2 increased the number of macrophages in lesions as well as concentrations of mRNAs encoded by Csf1, Nt3, and the tyrosine kinase neurotrophin receptor, TrkB. By using in vitro models, we determined that the treatment of rat dorsal root ganglia neurons with E2 increased mRNA concentrations of the chemokine C-C motif ligand 2 that stimulated migration of colony-stimulating factor 1-differentiated macrophages. Conversely, incubation of colony-stimulating factor 1 macrophages with E2 increased concentrations of brain-derived neurotrophic factor and neurotrophin 3, which stimulated neurite outgrowth from ganglia explants. In summary, we demonstrate a key rote for E2 in stimulating macrophage-nerve interactions, providing novel evidence that endometriosis is an estrogen-dependent neuroinflammatory disorder.