Department of Anesthesiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Department of Human Anatomy, Histology and Embryology, Institute of Basic Medical Sciences, Neuroscience Center, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China.
J Neuroinflammation. 2021 Mar 5;18(1):65. doi: 10.1186/s12974-020-02066-y.
As a classic innate immunity pathway, Toll-like receptor 4 (TLR4) signaling has been intensively investigated for its function of pathogen recognition. The receptor is located not only on immune cells but also on sensory neurons and spinal glia. Recent studies revealed the involvement of neuronal TLR4 in different types of pain. However, the specific role of TLR4 signaling in the pain symptom of endometriosis (EM) remains obscure.
The rat endometriosis model was established by transplanting uterine horn tissue into gastrocnemius. Western blotting and/or immunofluorescent staining were applied to detect high mobility group box 1 (HMGB1), TLR4, myeloid differentiation factor-88 adaptor protein (MyD88), and nuclear factor kappa-B-p65 (NF-κB-p65) expression, as well as the activation of astrocyte and microglia. The antagonist of TLR4 (LPS-RS-Ultra, LRU) and MyD88 homodimerization inhibitory peptide (MIP) were intrathecally administrated to assess the behavioral effects of blocking TLR4 signaling on endometriosis-related pain.
Mechanical hyperalgesia was observed at the graft site, while HMGB1 was upregulated in the implanted uterine tissue, dorsal root ganglion (DRG), and spinal dorsal horn (SDH). Compared with sham group, upregulated TLR4, MyD88, and phosphorylated NF-κB-p65 were detected in the DRG and SDH in EM rats. The activation of astrocytes and microglia in the SDH was also confirmed in EM rats. Intrathecal application of LRU and MIP alleviated mechanical pain on the graft site of EM rats, with decreased phosphorylation of NF-κB-p65 in the DRG and reduced activation of glia in the SDH.
HMGB1-TLR4-MyD88 signaling pathway in the DRG and SDH may involve in endometriosis-related hyperpathia. Blockade of TLR4 and MyD88 might serve as a potential treatment for pain in endometriosis.
作为经典的先天免疫途径，Toll 样受体 4（TLR4）信号已被深入研究，以了解其对病原体识别的功能。该受体不仅位于免疫细胞上，还位于感觉神经元和脊髓神经胶质上。最近的研究表明，神经元 TLR4 参与了不同类型的疼痛。然而，TLR4 信号在子宫内膜异位症（EM）疼痛症状中的具体作用仍不清楚。
通过将子宫角组织移植到腓肠肌中来建立大鼠子宫内膜异位症模型。应用 Western blot 和/或免疫荧光染色检测高迁移率族蛋白 B1（HMGB1）、TLR4、髓样分化因子 88 衔接蛋白（MyD88）和核因子 kappa-B-p65（NF-κB-p65）的表达以及星形胶质细胞和小胶质细胞的激活。鞘内给予 TLR4 拮抗剂（LPS-RS-Ultra，LRU）和 MyD88 同源二聚化抑制肽（MIP），以评估阻断 TLR4 信号对子宫内膜异位症相关疼痛的行为影响。
在移植物部位观察到机械性痛觉过敏，而在植入的子宫组织、背根神经节（DRG）和脊髓背角（SDH）中 HMGB1 上调。与假手术组相比，EM 大鼠的 DRG 和 SDH 中 TLR4、MyD88 和磷酸化 NF-κB-p65 上调。EM 大鼠 SDH 中星形胶质细胞和小胶质细胞的激活也得到了证实。鞘内给予 LRU 和 MIP 减轻了 EM 大鼠移植物部位的机械性疼痛，降低了 DRG 中 NF-κB-p65 的磷酸化，并减少了 SDH 中胶质细胞的激活。
DRG 和 SDH 中的 HMGB1-TLR4-MyD88 信号通路可能与子宫内膜异位症相关的痛觉过敏有关。阻断 TLR4 和 MyD88 可能成为子宫内膜异位症疼痛的潜在治疗方法。
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