Suppression of TLR4-MyD88 signaling pathway attenuated chronic mechanical pain in a rat model of endometriosis.
Suppression of TLR4-MyD88 signaling pathway attenuated chronic mechanical pain in a rat model of endometriosis.
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抑制 TLR4-MyD88 信号通路可减轻子宫内膜异位症大鼠模型的慢性机械性疼痛
DOI：
10.1186/s12974-020-02066-y
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发表时间：
2021-03-05
影响因子：
9.3
通讯作者：
Ma C
中科院分区：
文献类型：
--
作者：
Su W;Cui H;Wu D;Yu J;Ma L;Zhang X;Huang Y;Ma C
toll样受体4 （Toll-like receptor 4, TLR4）信号作为一种经典的先天免疫途径，其病原识别功能已被广泛研究。这种受体不仅存在于免疫细胞上，也存在于感觉神经元和脊髓胶质细胞上。最近的研究表明，神经元TLR4参与不同类型的疼痛。然而，TLR4信号在子宫内膜异位症（EM）疼痛症状中的具体作用尚不清楚。方法将子宫角组织植入腓肠肌，建立大鼠子宫内膜异位症模型。采用Western blot和/或免疫荧光染色检测高迁移率组盒1 （HMGB1）、TLR4、髓样分化因子-88适配蛋白（MyD88）、核因子κ b -p65 （NF-κB-p65）的表达以及星形胶质细胞和小胶质细胞的活化情况。我们在鞘内给予TLR4拮抗剂（LPS-RS-Ultra， LRU）和MyD88同二聚抑制肽（MIP），以评估阻断TLR4信号传导对子宫内膜异位症相关疼痛的行为影响。结果移植物部位出现机械性痛觉过敏，HMGB1在移植物子宫组织、背根神经节（DRG）和脊髓背角（SDH）中表达上调。与假手术组比较，EM大鼠DRG和SDH中TLR4、MyD88和NF-κB-p65的磷酸化水平均上调。在EM大鼠中也证实了SDH中星形胶质细胞和小胶质细胞的激活。鞘内应用LRU和MIP可减轻EM大鼠移植物部位的机械性疼痛，降低DRG中NF-κB-p65的磷酸化，降低SDH中胶质细胞的活化。结论DRG和SDH中shmgb1 - tlr4 - myd88信号通路可能参与子宫内膜异位症相关性超病变的发生。阻断TLR4和MyD88可能作为子宫内膜异位症疼痛的潜在治疗方法。
BackgroundAs 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.MethodsThe 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.ResultsMechanical 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.ConclusionsHMGB1-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.
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DOI：
10.1016/j.bbi.2014.06.199
发表时间：
2014-11
期刊：
Brain, behavior, and immunity
影响因子：
--
作者：
Allette YM;Due MR;Wilson SM;Feldman P;Ripsch MS;Khanna R;White FA
通讯作者：
White FA
影响因子：
8.8
作者：
Das N;Dewan V;Grace PM;Gunn RJ;Tamura R;Tzarum N;Watkins LR;Wilson IA;Yin H
通讯作者：
Yin H
影响因子：
4
作者：
Bestall SM;Hulse RP;Blackley Z;Swift M;Ved N;Paton K;Beazley-Long N;Bates DO;Donaldson LF
通讯作者：
Donaldson LF
影响因子：
2.7
作者：
Flyckt, Rebecca;Kim, Suejin;Falcone, Tommaso
通讯作者：
Falcone, Tommaso
影响因子：
3
作者：
Mazur, Curt;Fitzsimmons, Bethany;Wancewicz, Ed
通讯作者：
Wancewicz, Ed