Macrophage-derived netrin-1 contributes to endometriosis-associated pain

Shaojie Ding; Xinyue Guo; Libo Zhu; Jianzhang Wang; Tiantian Li; Qin Yu; Xinmei Zhang

doi:10.21037/atm-20-2161

Macrophage-derived netrin-1 contributes to endometriosis-associated pain

Ann Transl Med. 2021 Jan;9(1):29. doi: 10.21037/atm-20-2161.

Authors

Shaojie Ding¹, Xinyue Guo², Libo Zhu¹, Jianzhang Wang¹, Tiantian Li², Qin Yu¹, Xinmei Zhang¹

Affiliations

¹ Department of Gynecology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, China.
² Zhejiang University School of Medicine, Hangzhou, China.

Abstract

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; macrophage; netrin-1; pain; polarization.