Department of Neuroscience and Physiology, Dental Research Institute, BK21-Plus, School of Dentistry, Seoul National University, Seoul, Korea.
Department of Chemistry, Seoul National University, Seoul, Korea.
EMBO J. 2020 Mar 16;39(6):e102214. doi: 10.15252/embj.2019102214. Epub 2020 Feb 6.
Spinal cord microglia contribute to nerve injury-induced neuropathic pain. We have previously demonstrated that toll-like receptor 2 (TLR2) signaling is critical for nerve injury-induced activation of spinal cord microglia, but the responsible endogenous TLR2 agonist has not been identified. Here, we show that nerve injury-induced upregulation of sialyltransferase St3gal2 in sensory neurons leads to an increase in expression of the sialylated glycosphingolipid, GT1b. GT1b ganglioside is axonally transported to the spinal cord dorsal horn and contributes to characteristics of neuropathic pain such as mechanical and thermal hypersensitivity. Spinal cord GT1b functions as an TLR2 agonist and induces proinflammatory microglia activation and central sensitization. Pharmacological inhibition of GT1b synthesis attenuates nerve injury-induced spinal cord microglia activation and pain hypersensitivity. Thus, the St3gal2-GT1b-TLR2 axis may offer a novel therapeutic target for the treatment of neuropathic pain.
脊髓小胶质细胞有助于神经损伤引起的神经性疼痛。我们之前已经证明， Toll 样受体 2（TLR2）信号对于神经损伤引起的脊髓小胶质细胞激活至关重要，但负责的内源性 TLR2 激动剂尚未确定。在这里，我们表明，神经损伤诱导的感觉神经元中唾液酸转移酶 St3gal2 的上调导致唾液酸化糖脂 GT1b 的表达增加。 GT1b 神经节苷脂被轴突运输到脊髓背角，并有助于神经性疼痛的特征，如机械和热敏感性。脊髓 GT1b 作为 TLR2 激动剂，诱导促炎小胶质细胞激活和中枢敏化。 GT1b 合成的药理学抑制减轻了神经损伤引起的脊髓小胶质细胞激活和痛觉过敏。因此，St3gal2-GT1b-TLR2 轴可能为治疗神经性疼痛提供新的治疗靶点。
