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

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

  • Inflamm Res. 2025 Feb 19;74(1):42. doi: 10.1007/s00011-025-02010-x.
Jue Li 1 2 3,  Zhijing Wu 1 2,  Nan Li 1 2,  Jianhong Wang 1 2,  Meihua Huang 1 2,  Li Zhu 1 2,  Guiping Wan 4 5,  Zhenzhen Zhang 6 7
Affiliations

Affiliations

  • 1 Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Jiangsu, 210028, Nanjing, China.
  • 2 Jiangsu Province Academy of Traditional Chinese Medicine, Jiangsu, 210028, Nanjing, China.
  • 3 Kunshan Hospital Affiliated to Nanjing University of Chinese Medicine, Jiangsu, 215300, Kunshan, China.
  • 4 Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Jiangsu, 210028, Nanjing, China. wanguiping@263.net.
  • 5 Jiangsu Province Academy of Traditional Chinese Medicine, Jiangsu, 210028, Nanjing, China. wanguiping@263.net.
  • 6 Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Jiangsu, 210028, Nanjing, China. zhenzhen_0618@163.com.
  • 7 Jiangsu Province Academy of Traditional Chinese Medicine, Jiangsu, 210028, Nanjing, China. zhenzhen_0618@163.com.
PMID: 39969583 DOI: 10.1007/s00011-025-02010-x
Abstract

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.

Keywords

Endometriosis; IL-33; Inflammation; Macrophages; Pain.

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