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Macrophage and Nerve Interaction in Endometriosis Jinjie Wu1, Hongyu Xie1, Shuzhong Yao2 and Yanchun Liang2*

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Macrophage and Nerve Interaction in Endometriosis Jinjie Wu1, Hongyu Xie1, Shuzhong Yao2 and Yanchun Liang2* Wu et al. Journal of Neuroinflammation (2017) 14:53 DOI 10.1186/s12974-017-0828-3 REVIEW Open Access Macrophage and nerve interaction in endometriosis Jinjie Wu1, Hongyu Xie1, Shuzhong Yao2 and Yanchun Liang2* Abstract Dysregulation of the immune system in endometriotic milieus has been considered to play a pivotal role in the pathogenesis of endometriosis. Macrophage recruitment and nerve fiber infiltration are the two major characteristics of this aberrant immune environment. First, the recruitment of macrophages and their polarization phenotype within the endometriotic lesion have been demonstrated to facilitate the development and maintenance of endometriosis. M1 phenotype of macrophages has the capacity to secrete multiple cytokines for inflammatory response, while M2 macrophage possesses an opposite property that can mediate the process of immunosuppression and neuroangiogenesis. Upon secretion of multiple abnormal signal molecules by the endometriotic lesion, macrophages could alter their location and phenotype. These changes facilitate the accommodation of the aberrant microenvironment and the exacerbation of disease progression. Second, the infiltration of nerve fibers and their abnormal distribution are proved to be involved in the generation of endometriosis-associated pain and inflammatory response. An imbalance in sensory and sympathetic innervation and the abnormal secretion of different cytokines could mediate neurogenesis and subsequent peripheral neuroinflammation in endometriosis. Although endometriosis creates an inflammatory milieu promoting macrophage infiltration and an imbalanced innervation, interaction between macrophages and nerve fibers in this process remains unknown. The aim of this review is to highlight the role of macrophage and nerve interaction in endometriosis, where macrophage recruitment and neurogenesis can be the underlying mechanism of neuroinflammation and pathogenesis of endometriosis. Keywords: Macrophage, Nerve fiber, Neurogenesis, Neuroinflammation, Endometriosis Background endometrial debris on the peritoneum of patients with Endometriosis is defined as the presence of the endometriosis [4, 5]. Tissue degeneration of retrograde endometrial-like tissue (lesion) outside the uterus, which menstruation plays a central role in triggering inflamma- is commonly found on the peritoneum, and sometimes tory pain in endometriosis through the activation of as a subsequent invasion into the underlying tissue. It is innate immune cells and peripheral nerve ending [6]. In a common gynecological disease affecting 10% of repro- their opinion, the activation of the innate immune sys- ductive age women [1] and is found in up to 20–40% of tem is the first important step in the pathophysiology of infertile women [2]. Endometriosis often causes dysmen- endometriosis. Macrophages, mast cells, neutrophils, orrhea, pelvic pain, and infertility, which poses a severe and mature dendritic cells are activated by menstrual health threat on women and teenage girls’ life [3]. debris and subsequently participate in the inflammatory Though scholars have put forward many hypotheses for process, while macrophages are the primary contributor the pathogenesis of endometriosis [4], the exact mechan- of pro-inflammatory chemotactic cytokines and major ism still remains uncertain. source of neuroangiogenesis among them [7]. The recruit- Growing evidence tend to focus on the dysregulation ment and functional changes of macrophages [8], the migra- of immune response stimulated by the presence of tion of endothelial cells and subsequent neovascularization [9], and the abnormal generation and distribution of * Correspondence: [email protected] nerve fibers [10] in the lesion are essential events contrib- 2Department of Obstetrics and Gynecology, First Affiliated Hospital of Sun Yat-sen University, No. 58, the 2nd Zhongshan Road, Yuexiu District, uting to the dysregulation of endometriosis. Notably, Guangzhou 510080, Guangdong Province, China macrophages are important immune cells that can produce Full list of author information is available at the end of the article © The Author(s). 2017 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. Wu et al. Journal of Neuroinflammation (2017) 14:53 Page 2 of 11 both pro-inflammatory and anti-inflammatory cytokines. classically or alternatively activated phenotypes based The recruitment and distribution of macrophages within on their receptor composition, secretion profile, and re- the endometriotic lesion have been demonstrated to facili- sponse to the external stimuli [22–24]. Classical acti- tate and maintain endometriosis in patients [11–13]. And vated phenotype, also called M1 macrophages, are nerve fibers in endometriosis also play a crucial role. As the activated by interferon gamma (IFN-γ), tumor necrosis endometriotic lesion develops its own innervation, it is factor alpha (TNF-α), or lipopolysaccharide (LPS) [22, 23]. proved to be involved in the generation of pain and inflam- As a consequence, M1 macrophages could produce mation. Imbalance of sensory and sympathetic nerve fibers pro-inflammatory cytokines and chemokines participat- has also been identified within the endometriotic lesion [14, ing in the early stage of injury, pro-inflammatory response, 15], specifically related to the inflammatory response in the and myoblast proliferation [25]. In contrast, alternatively lesion. activated macrophages or M2 macrophages are activated Although the infiltration of macrophages and nerve fi- by IL-4, IL-10, IL-13, or transforming growth factor-β bers coexist in endometriosis, it remains unknown whether (TGF-β) [26, 27]. Once activated, M2 macrophages se- there is a cross-talk between them. Inflammation and crete anti-inflammatory cytokines, growth factors, and neurogenesis are two main factors mediating the pathogen- other reparative factors [25], which are involved in the esis of endometriosis. But they are not independent of each anti-inflammatory response, an advanced stage of the other [16]. More importantly, the macrophage can migrate repair and healing process. In short, M1 macrophages toward the nerve [17], further indicating a specific inter- can kill tumor cells and clear pathogens by activating action between the macrophage and nerve in endometri- inflammatory or immune responses, whereas M2 macro- osis. Also, this interaction could be enhanced by estradiol phages are immunosuppressive cells that promote tissue in the peritoneal endometriosis [18]. It is believed that this repair, tumor angiogenesis, tumor growth, and tumor interaction could probably contribute to the pathogenesis progression [23]. of endometriosis. But the molecular mechanism of this As mentioned above, macrophages can exhibit high interaction is still elusive. Therefore, it is important to in- plasticity and different functional profiles. Thus, it is vestigate the mechanism of the interaction between macro- possible for the macrophage to be polarized toward a phages and nerve fibers in endometriosis. Target therapy proper phenotype once stimulated by the signals triggered toward the interaction of macrophages and nerves can not by the lesion. For example, tumor-associated macrophages only interfere to the process of inflammation and the (TuAMs) can polarize to M2 phenotype for tumor angio- activity of peripheral nerves but also remit the progression genesis, growth, and metastasis [28, 29]. With an opposite of endometriosis. The aim of this review is to highlight the stimulus, TuAMs can also polarize toward M1 phenotype potential role of macrophage and nerve interaction in to exhibit inhibition of tumor growth and progression endometriosis in detail. Theoretical elaboration of the [30, 31]. This discovery suggests that polarization of the underlying mechanism provides a new insight for the macrophage is probably associated with pathogenesis pathogenesis of endometriosis. and progression of the disease. There have been many studies demonstrating the ab- Macrophages and their phenotypes in normal distribution of macrophages within the endome- endometriosis triotic lesion of patients with endometriosis [13, 32, 33]. Macrophages are mononuclear phagocytes. Most of Macrophages in peritoneal fluid and endometriotic them originate from the progenitor in the bone marrow lesion can express markers of alternative activated [19]. Once released from the blood vessels, macrophages phenotype, from both human specimens and mouse migrate into the tissue associated with their differenti- models [34]. Human endometrial macrophages are pre- ation into distinct population depending on the anatom- dominantly M2 macrophages [35]. The abnormal endo- ical location and the microenvironment of the lesion. metriotic milieu can induce the M2 polarization of Each population of macrophage in specific tissue has a macrophages leading to the development and invasive- distinct functional profile and gene expression pattern ness of endometrial stromal cells [36]. In contrast, one [20]. Different
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