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Macrophage-Derived Netrin-1 Contributes to Endometriosis- Associated Pain

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Macrophage-Derived Netrin-1 Contributes to Endometriosis- Associated Pain 29 Original Article Page 1 of 16 Macrophage-derived netrin-1 contributes to endometriosis- associated pain Shaojie Ding1, Xinyue Guo2, Libo Zhu1, Jianzhang Wang1, Tiantian Li2, Qin Yu1, Xinmei Zhang1^ 1Department of Gynecology, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, China; 2Zhejiang University School of Medicine, Hangzhou, China Contributions: (I) Conception and design: S Ding, X Guo, X Zhang; (II) Administrative support: X Zhang; (III) Provision of study materials or patients: S Ding, L Zhu, J Wang; (IV) Collection and assembly of data: S Ding, T Li, Q Yu; (V) Data analysis and interpretation: X Guo, L Zhu, J Wang; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. Correspondence to: Xinmei Zhang, MD, PhD. Department of Gynecology, Women’s Hospital, School of Medicine, Zhejiang University, 1 Xueshi Road, Hangzhou 310006, China. Email: [email protected]. Background: Endometriosis-associated pain can be considered a type of neuropathic pain. Netrin-1 is an axon guidance cue that regulates axonal attraction or rejection in neural injury and regeneration. However, whether netrin-1 plays a role in endometriosis-associated pain remains unclear. This study aimed to determine the role of netrin-1 in endometriosis-related pain. Methods: Peripheral blood, peritoneal fluid, and endometrial tissues were sampled from women with (n=37) and without endometriosis (n=23). Lipopolysaccharide (LPS) and interferon gamma (IFN-γ) were used to stimulate human monocytic cell lines (THP-1) and rat alveolar macrophage-derived cell lines (NR8383) to induce M1 phenotype macrophages. Serum netrin-1 concentrations, endometrial expression levels of netrin-1, and its receptors including deleted in colorectal cancer (DCC), A2B adenosine receptor (A2BAR), uncoordinated B receptor (UNC5B), uncoordinated C receptor (UNC5C) and Down’s syndrome cell adhesion molecule (DSCAM) were assessed. The polarization phenotypes of the peritoneal macrophages were identified by detecting the marker expression of M1/M2 macrophages via flow cytometry. The expression levels of M1 markers and netrin-1 in THP-1/NR8383 cells were determined. Results: The expression levels of netrin-1 in serum and endometriotic lesions were significantly higher in women with endometriosis, and were positively correlated with the severity of endometriosis-associated pain. Netrin-1 was co-expressed with CD68 (a macrophage marker) in endometriotic lesions and was synthesized and secreted by THP-1 and NR8383 cells in the process of M1 polarization. In women with endometriosis, peritoneal macrophages were polarized towards the M1 phenotype. In addition, increased expression of DCC and A2BAR, and decreased expression of UNC5B, UNC5C and DSCAM were found in endometriotic lesions. Conclusions: These results suggest that netrin-1 production by macrophages in endometriotic lesions may play an important role in endometriosis-associated pain. Keywords: Endometriosis; pain; netrin-1; macrophage; polarization Submitted Mar 04, 2020. Accepted for publication Oct 10, 2020. doi: 10.21037/atm-20-2161 View this article at: http://dx.doi.org/10.21037/atm-20-2161 ^ ORCID: 0000-0001-6474-3477. © Annals of Translational Medicine. All rights reserved. Ann Transl Med 2021;9(1):29 | http://dx.doi.org/10.21037/atm-20-2161 Page 2 of 16 Ding et al. Netrin-1 in endometriosis-associated pain Introduction receptor (A2BAR) (21-24). It has been demonstrated that netrin-1, the most studied Endometriosis is a common gynecological disease guidance cue, triggers an attraction effect through DCC and characterized by pain and infertility, which affects women neogenin, or a repulsion effect via UNC5 A-D (17). In the of childbearing age (1). Pain symptoms in patients with central nervous system, netrin 1 is secreted by ventricular endometriosis include dysmenorrhea, dyspareunia, dysuria, zone neural progenitors and floor-plate cells in the ventral defecation pain and chronic pelvic pain, all of which have a embryonic spinal cord (25,26). In the process of peripheral significant impact on women’s quality of life (2). However, neural injury and regeneration, increased levels of netrin-1 despite extensive research efforts, the exact mechanisms of are mainly produced by Schwann cells (27). Netrin-1 endometriosis-associated pain remain unclear (3,4). expression has also been found to be increased in hypoxic In 2000, Anaf et al. were first to report S100-labeled conditions (24), and in inflammatory and other disease nerves infiltrating in endometriotic lesions, with the conditions such as obesity (28), type 2 diabetes (29), acute percentage of nerves being significantly higher in the lesions lung injury (30), atherosclerosis (31) and abdominal aortic of women who suffered severe endometriosis-associated pain (5). In subsequent studies, elevated specific makers aneurysm (AAA) (32). However, it is not clear whether for sensory, sympathetic, and parasympathetic nerves (6-8) netrin-1 is involved in the pathogenesis of endometriosis. and growth factors such as nerve growth factor (NGF), Co-localization of netrin-1 and CD68, a marker of brain derived neurotrophic factor (BDNF) and neurite macrophages, has been identified in atherosclerotic growth factor 2 (NEGF2) (9-13) were identified in different plaques (31), adipose tissues (28) and inflamed aortic vessel types of endometriotic lesions, all of which correlated with walls (32), suggesting that macrophages may participate in endometriosis-associated pain. Therefore, endometriosis- inflammation by secreting netrin-1. In fact, the inflammatory associated pain was considered to be a type of neuropathic microenvironment of endometriosis can promote macrophage pain. Moreover, in a rat model of endometriosis, auto- infiltration (33,34), which plays a crucial role in the etiology transplanted endometriotic lesions were shown to develop and pathogenesis of this disease including inflammatory autonomic and sensory innervation (14). In other studies, response (35), angiogenesis (34), proliferation (36) and growth-associated protein 43 (GAP-43), a marker for neurogenesis (37). The interaction between macrophages neurite outgrowth and regeneration, was expressed in nerve and nerve fibers contributes to neuroinflammation and fibers infiltrating in the endometriotic lesions of peritoneal pain generation in endometriosis (37). A large number and deep infiltrating endometriosis (15,16). However, it is of up-regulated molecules released by nerve fibers in still unclear how the nerve fibers in endometriotic lesions endometriotic lesions such as monocyte chemotactic sprout abnormally. protein-1 (MCP-1), colony-stimulating factor 1 (CSF-1) Netrins are members of the laminin superfamily which and leukemia inhibitory factor (LIF), are responsible for share a similar amino acid terminal sequence (17). The name the recruitment of macrophages from vessels within the netrin is derived from the Sanskrit word “netr”, meaning lesions (38,39). Conversely, infiltrating macrophages in “to guide”, because of their role in axon guidance (18). the lesions can in turn mediate neurogenesis by secreting Until now, three secreted netrins (netrins 1, 3 and 4), and neurotrophins, semaphorins, and vascular epithelial growth two glycosylphosphatidylinositol-anchored membrane factor (VEGF) (37,39,40). Macrophage activation is proteins, netrins G1 and G2, have been identified closely associated with endometriosis. However, whether in mammals. Netrin Gs regulate axon guidance by macrophages differentiate into classically activated forming synaptic interactions between neurons with the macrophages (pro-inflammatory, M1) or alternatively transmembrane netrin G ligands NGL1 and 2. The secreted activated macrophages (anti-inflammatory, M2) (41) remains netrins can bind to the receptors of deleted in colorectal highly debated, as does the issue of polarization of M1/M2 cancer (DCC), neogenin or uncoordinated (UNC5) A–D, macrophages in endometriosis (33,34,42,43), Therefore, it causing axonal attraction or rejection (19,20). Recent studies is important to explore the role of macrophage-mediated have shown that netrins also participate in angiogenesis, cell netrin-1 in the pathogenesis of endometriosis. proliferation, migration and tumorigenesis by binding to the In the present study, we aimed to investigate the role receptors of DCC, neogenin, UNC5, Down’s syndrome cell of macrophage-mediated netrin-1 in endometriosis- adhesion molecule (DSCAM), CD146 and A2B adenosine associated pain. Firstly, we detected expressions of netrin-1 © Annals of Translational Medicine. All rights reserved. Ann Transl Med 2021;9(1):29 | http://dx.doi.org/10.21037/atm-20-2161 Annals of Translational Medicine, Vol 9, No 1 January 2021 Page 3 of 16 and its receptors in endometriotic lesions. Secondly, we tissues were collected during the surgical procedure. The localized netrin-1 and macrophages in endometriotic blood or cell supernatants were centrifuged at 1,000 g for lesions. Thirdly, we determined polarization phenotypes of 10 minutes, and the supernatants were transferred into peritoneal macrophages. Lastly, we observed the expression 1.5 mL tubes and stored at −80 until processing. Of the and secretion of netrin-1 after macrophage M1 polarization 37 women with endometriosis, 16 (43.2%) had ovarian ℃ was induced in vitro. endometriosis, 11 (29.7%) had peritoneal endometriosis We present the following article in accordance with the and 10 (27.0%) had deeply infiltrating endometriosis. MDAR checklist
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