Li Jue, Wu Zhijing, Li Nan, Wang Jianhong, Huang Meihua, Zhu Li, Wan Guiping, Zhang Zhenzhen
Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Jiangsu, 210028, Nanjing, China.
Jiangsu Province Academy of Traditional Chinese Medicine, Jiangsu, 210028, Nanjing, China.
Inflamm Res. 2025 Feb 19;74(1):42. doi: 10.1007/s00011-025-02010-x.
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.
子宫内膜异位症是一种持续性炎症疾病，与盆腔或腹部疼痛相关。免疫系统和感觉神经系统在疼痛调节方面表现出协同作用。特别是，白细胞介素-33（IL-33）作为一种危险信号释放，并驱动严重子宫内膜异位症的关键特征。为了探究IL-33在子宫内膜异位症相关疼痛中的作用机制，我们利用了体内小鼠子宫内膜异位症模型以及RAW 264.7细胞和背根神经节（DRG）神经元的体外实验。在体内，我们证明IL-33显著加剧了小鼠的子宫内膜异位症并诱导了痛觉过敏。通过与巨噬细胞中的ST2受体相互作用，IL-33增强了肿瘤坏死因子α（TNF-α）和白细胞介素1β（IL-1β）的释放。这一过程引发了炎症级联反应，进一步促进了异位病灶中巨噬细胞的募集和神经发生。作为伤害感受器表达的一种离子通道，在存在IL-33的情况下，背根神经节中瞬时受体电位香草酸受体1（TRPV1）的表达显著增加。在体外，我们证实IL-33提高了巨噬细胞中TNF-α的释放。最终，巨噬细胞衍生的TNF-α通过TNFR1/p38 MAPK信号通路增加了DRG神经元细胞中TRPV1蛋白水平。总体而言，这些结果揭示了IL-33在子宫内膜异位症相关疼痛中的诱导作用，并突出了巨噬细胞与感觉神经元之间的相互作用。
