Department of Health Science, Clinical Pharmacology and Oncology Section, University of Florence, Florence, Italy.
Department of Health Science, Obstetrics and Gynecology Section, University of Florence, Florence, Italy.
Nat Commun. 2024 Nov 25;15(1):10142. doi: 10.1038/s41467-024-54486-6.
Over 60% of women with endometriosis experience abdominopelvic pain and broader pain manifestations, including chronic back pain, fibromyalgia, chronic fatigue, vulvodynia, and migraine. Although the imbalance of proinflammatory mediators, including the complement component C5a, is associated with endometriosis-related pain, the mechanisms causing widespread pain and the C5a role remain unclear. Female mice and women with endometriosis exhibit increased plasma C5a levels and pain. We hypothesize the Schwann cells involvement in endometriotic pain. Here, we show that silencing the C5a receptor (C5aR1) in Schwann cells blocks the C5a-induced activation of the NLRP1 inflammasome and subsequent release of interleukin-1β (IL-1β). Macrophages, recruited to sciatic/trigeminal nerves by IL-1β from Schwann cells, increase oxidative stress, which activates the proalgesic TRPA1 pathway, resulting in widespread pain. These findings reveal a pathway involving Schwann cell C5aR1, NLRP1/IL-1β activation, macrophage recruitment, oxidative stress, and TRPA1 engagement, contributing to pain in a mouse model of endometriosis.
超过 60%的子宫内膜异位症患者会出现腹盆腔疼痛和更广泛的疼痛表现，包括慢性背痛、纤维肌痛、慢性疲劳、外阴痛和偏头痛。虽然包括补体成分 C5a 在内的促炎介质失衡与子宫内膜异位症相关疼痛有关，但导致广泛疼痛的机制和 C5a 的作用仍不清楚。患有子宫内膜异位症的雌性小鼠和女性表现出血浆 C5a 水平升高和疼痛增加。我们假设雪旺细胞参与子宫内膜异位症疼痛。在这里，我们表明，沉默雪旺细胞中的 C5a 受体（C5aR1）可阻断 C5a 诱导的 NLRP1 炎性小体的激活以及随后白细胞介素-1β（IL-1β）的释放。IL-1β 从雪旺细胞募集到坐骨/三叉神经的巨噬细胞增加氧化应激，这激活了致痛性 TRPA1 途径，导致广泛疼痛。这些发现揭示了一种涉及雪旺细胞 C5aR1、NLRP1/IL-1β 激活、巨噬细胞募集、氧化应激和 TRPA1 参与的途径，导致子宫内膜异位症小鼠模型中的疼痛。
