Exploring macrophage and nerve interaction in endometriosis-associated pain: the inductive role of IL-33

Endometriosis, a persistent inflammatory disease, is associated with pelvic or abdominal pain. The immune system and sensory nervous system show a synergistic effect on regulation of pain. In particular, Interleukin-33 (IL-33) is released as a danger signal and drives key hallmarks of severe endometriosis. To explore the mechanistic involvement of IL-33 in pain associated with endometriosis, both an in vivo murine endometriosis model and in vitro experiments with RAW 264.7 cells and dorsal root ganglion (DRG) neurons were utilized. In vivo, we demonstrated that IL-33 significantly exacerbated endometriosis and induced hyperalgesia in mice. By interacting with the ST2 receptor in macrophages, IL-33 enhanced the release of tumor necrosis factor α (TNF-α) and Interleukin 1β (IL-1β). This process set off an inflammatory cascade, which further facilitated macrophages recruitment and neurogenesis in ectopic lesions. As an ion channel expressed by nociceptors, transient receptor potential vanilloid 1 (TRPV1) expression was significantly increased in DRG in the presence of IL-33. In vitro, we confirmed that IL-33 elevated the release of TNF-α in macrophages. Ultimately, macrophage-derived TNF-α increased TRPV1 protein level in DRG neuronal cells through the TNFR1/p38 MAPK signaling pathway. Overall, these results revealed an inductive role of IL-33 in pain associated with endometriosis, and highlighted the interaction between macrophages and sensory neurons. Similar content being viewed by others Data availability No datasets were generated or analysed during the current study.

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The present study was funded by grants from the National Natural Science Foundation of China (No. 82074319 and 82174420) and Independent scientific research project of Jiangsu Province Academy of Traditional Chinese Medicine (No. BM2018024-2019007). Author information Authors and Affiliations Contributions JL: Conceptualization, writing original draft preparation. ZW, NL: Investigation, software, JW, MH and LZ: methodology, statistical analysis. GW and ZZ: Reviewing and editing, funding acquisition, supervision. All authors read and approved the final manuscript. Corresponding authors Ethics declarations Conflict of interest The authors declared no conflict of interest. Additional information Responsible Editor: Thiago Cunha. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Electronic supplementary material Below is the link to the electronic supplementary material. Rights and permissions Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. About this article Cite this article Li, J., Wu, Z., Li, N. et al. Exploring macrophage and nerve interaction in endometriosis-associated pain: the inductive role of IL-33. Inflamm. Res. 74, 42 (2025). https://doi.org/10.1007/s00011-025-02010-x Received: Revised: Accepted: Published: Version of record: DOI: https://doi.org/10.1007/s00011-025-02010-x