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Villainous Role of Estrogen in Macrophage-Nerve Interaction In Liang et al. Reproductive Biology and Endocrinology (2018) 16:122 https://doi.org/10.1186/s12958-018-0441-z REVIEW Open Access Villainous role of estrogen in macrophage- nerve interaction in endometriosis Yanchun Liang1, Hongyu Xie2, Jinjie Wu2, Duo Liu1 and Shuzhong Yao1* Abstract Endometriosis is a complex and heterogeneous disorder with unknown etiology. Dysregulation of macrophages and innervation are important factors influencing the pathogenesis of endometriosis-associated pain. It is known to be an estrogen-dependent disease, estrogen can promote secretion of chemokines from peripheral nerves, enhancing the recruitment and polarization of macrophages in endometriotic tissue. Macrophages have a role in the expression of multiple nerve growth factors (NGF), which mediates the imbalance of neurogenesis in an estrogen-dependent manner. Under the influence of estrogen, co-existence of macrophages and nerves induces an innovative neuro-immune communication. Persistent stimulation by inflammatory cytokines from macrophages on nociceptors of peripheral nerves aggravates neuroinflammation through the release of inflammatory neurotransmitters. This neuro-immune interaction regulated by estrogen sensitizes peripheral nerves, leading to neuropathic pain in endometriosis. The aim of this review is to highlight the significance of estrogen in the interaction between macrophages and nerve fibers, and to suggest a potentially valuable therapeutic target for endometriosis-associated pain. Keywords: Estrogen, Macrophage, Nerve fiber, Neuroinflammation, Endometriosis Introduction the aberrant distribution of nerves, impairment of Endometriosis is a common gynecological disorder, which immune microenvironment in the peritoneal cavity induces is defined as the presence of the endometrial-like tissue inflammation which can also mediate endometriosis-as- outside the uterine cavity [1]. This chronic inflammatory sociated pain [8]. Endometriosis-associated inflammation disease affects 6–10% of women during reproductive age is able to stimulate and sensitize peripheral nerves. Re- [2], and 30 to 50% are accompanied with pelvic pain and is searchers found that activation of (DRG) mast cells by es- associated with infertility [3, 4]. Though extensive research trogen can trigger the release of NGF and also sensitize hasproposedmanytheoriesforthepathogenesisof dorsal root ganglion cells [9]. This neuroimmune inter- endometriosis, the mechanism of endometriosis-associated action mediated by estrogen is correlated with the severity pain still remains elusive. As an estrogen-dependent disease, of endometriosis-associated dysmenorrhea. Among the local levels of estrogen in the menstrual blood and periton- dysregulated immune components, macrophages are one eal fluids are higher in patients with endometriosis in com- of the most numerous immune cells in endometriotic parisontohealthywomen[5]. Estrogen exhibits a pivotal lesions [10]. The concentration and proportion of role in the maintenance of endometriosis-associated pain. macrophage are significantly increased in peritoneal Growing evidences support that the presence of fluid of women with endometriosis [11, 12], indicating endometriosis-associated nerve fibers is related to the their involvement in the development of pain. A recent severity of dysmenorrhea [6]. Studies have confirmed the study exhibits the critical role of estrogen in mediating the presence and high expression of sensory, sympathetic and communication between macrophage and nerve fibers in parasympathetic nerve fibers in peritoneal lesion in endometriosis [13]. However, as an estrogen-dependent comparison to the normal peritoneum [7]. In addition to disease, the exact mechanism of estrogen regulating the cross talk between macrophages and nerve fibers in endo- * Correspondence: [email protected] metriosis is ambiguous. 1Department of Obstetrics and Gynecology, First Affiliated Hospital, Sun Yat-sen University, No. 58, the 2nd Zhongshan Road, Yuexiu District, The aim of this review is to highlight the potential role of Guangzhou, Guangdong Province, China estrogen in maintaining the cross talk between macrophages Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Liang et al. Reproductive Biology and Endocrinology (2018) 16:122 Page 2 of 11 and nerve fibers in endometriosis. Theoretical elaboration of CEBPβ. Further study characterizes the heterogeneous the underlying mechanism provides a new insight into the expression of ERs in different types of endometriosis. pathogenesis of endometriosis and a potential therapeutic Ovarian lesions show the lowest expression of ERα and targets for treatment. the highest expression of ERβ,whereasthefallopian tube lesions show a high expression of both receptors [27]. The role of estrogen and their receptors in The largest ERβ to ERα ratio is observed in ovarian lesions endometriosis compared with peritoneal, fallopian tube, and extra pelvic Estrogen has a central role in endometriosis. It can lesions. Moreover, aberrant expression of ERα and ERβ facilitate disease progression mainly through binding are both correlated to the production of proinflammatory different estrogen receptors (ER) [14]. The ERs can be cytokines in endometriosis [28]. The combinational classically divided into two subtypes: ERα and ERβ, both interaction of ERβ with caspase 1 and NLR family pyrin act as nuclear transcription factors [15]. ERα is mainly domain-containing 3 (NALP3) activates caspase 1 and responsible for the modulation of cell growth related subsequently elevates the level of IL-1β in ectopic lesions, genes [16], whereas ERβ plays an important role in cell enhancing the inflammation in the endometriotic micro- cycle progression and apoptosis. Further studies reveal an- environment [21]. In addition, the expression of GPER is other subtype of estrogen receptor, membrane-association also significantly increased in ectopic endometrium G-protein coupled estrogen receptor (GPER) in the cell compared to eutopic endometrium [29], which specific- menmbrane, which is able to mediate the rapid non-gen- ally promotes the proliferation of endometrial fragment. omic effects of estrogen [17]. GPER is reported to be cap- Although abnormal expression of different ERs has able of activating several downstream molecules, such as been identified in endometriotic lesion, their functions ERK1/2, PI3K, PKC and calcium ion channels [17]. These involved in the pathogenesis of endometriosis are far studies suggest that different signaling pathways are acti- from clarified. vated by different kinds of ER, exhibiting their distinct function. As a result, the action of estrogen on endometri- Characteristics of estrogen receptors in macrophages of osis is closely related to the types of receptors and their endometriosis distribution. As discussed above, activation of the estrogen receptors can induce inflammatory events. In the endometriotic Distribution of estrogen receptors in endometriosis microenvironment, multiple immune cells, such as mac- Different estrogen receptors have abnormal distribution rophages, mast cells, neutrophils, and mature dendritic in the ectopic endometrium of women with endometriosis cells are mobilized by the retrograded endometrial cells. [18]. A higher ERβ and a lower ERα expression profile in Among them, macrophages are the primary contributor endometriotic lesions have been proposed as a major of pro-inflammatory cytokines and chemokines [30]. Both background of estrogen action in endometriosis [19]. ERα and ERβ are significantly overexpressed in macro- Several studies have shown significantly elevated ERβ phages of endometriosis [28]. Treatment with 17β-estradiol levels and decreased ERα levels in endometriotic stromal in human macrophages in vitro induces an increase of ERα cells and tissues compared to the eutopic endometrium expression in macrophages. Furthermore, the estrogen-ER [20]. ERβ-induced the formation of ASK-1/STRAP com- interaction can up-regulate the production of IL-6 and plex can prevent the activation of tumor necrosis factor α TNFα from lipopolysaccharide (LPS)-activated macro- (TNFα)-mediated apoptosis in endometriotic tissues [21]. phages [31]. Specifically, macrophages with overexpres- Increased expression of Ras-like and estrogen-regulated sion of ERβ in endometriotic lesions have been shown growth inhibitor (RERG) has also been identified after the to exhibit enhanced phagocytic activity, and secrete activation of ERβ [22]. ERβ binds to the promoter regula- inflammatory cytokines including IL1β,TNFα and IL6 tory region of RERG, inducing gene expression of RERG, [21, 32]. Deficiency of ERα,butnotERβ,increased and then enhancing the proliferation of endometriotic TNFα production by mouse peritoneal macrophages in cells. Moreover, multiple molecules in endometriosis are response to bacterial stimuli, indicating a prominent able to stimulate the expression of ERβ, such
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