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

Shaojie Ding, Xinyue Guo, Libo Zhu, Jianzhang Wang, Tiantian Li, Qin Yu, Xinmei Zhang
Annals of translational medicine · 2021 · vol. 9(1) , pp. 29 · doi:10.21037/atm-20-2161 · PMID:33553322 · PMC7859736 · W3108580235
article OA: gold CC0 ⤵ 13 in-corpus citations
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⚙ AI-generated summary by claude@2026-06, 2026-06-09 ⓘ

This study found that netrin-1 levels are elevated in women with endometriosis and correlate with pain severity, suggesting macrophage-derived netrin-1 contributes to endometriosis-associated pain.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-10 ⓘ

This study investigated whether macrophage-derived netrin-1 contributes to endometriosis-associated pain by analyzing netrin-1 and its receptors in endometriotic lesions from 60 women undergoing laparoscopic surgery, comparing endometriosis (n=37) versus non-endometriosis benign gynecologic disease controls (n=23), and linking tissue findings with pain severity measured by VAS. Using immunohistochemistry and double immunofluorescence, the authors localized netrin-1 and macrophages in lesions, assessed peritoneal macrophage polarization by flow cytometry (M1 vs M2 markers), and performed in vitro experiments to measure netrin-1 expression and secretion after inducing macrophage M1 polarization, with serum/culture netrin-1 quantified by ELISA alongside mRNA/protein analyses. A stated caveat is that macrophage polarization in endometriosis is debated and polarization phenotypes can be complex, which may limit how directly M1/M2 categories map onto in vivo biology. This paper is centrally about endometriosis — specifically, macrophage-derived netrin-1 as a mechanism for endometriosis-associated pain.

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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.

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endometriosis

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