State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China.
Beijing Key Laboratory of Drug Target Identification and New Drug Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China.
Inflammation. 2022 Apr;45(2):838-850. doi: 10.1007/s10753-021-01588-8. Epub 2021 Nov 2.
TLR4 signal activated by lipopolysaccharide (LPS) is involved in the pathological process of the central nervous system (CNS) diseases and the suppression of TLR4 signal may become an effective treatment. TLR4-IN-C34, a TLR4 inhibitor, is expected to become a candidate compound with anti-neuroinflammatory response. In the present study, the anti-neuroinflammatory effects and possible mechanism of TLR4-IN-C34 were investigated in BV2 microglia cells stimulated by LPS. The results showed that TLR4-IN-C34 decreased the levels of pro-inflammatory factors and chemokines including NO, TNF-α, IL-1β, IL-6, and MCP-1 in the supernatant of LPS-stimulated BV2 cells. Further research indicated that TLR4-IN-C34 suppressed the expression or phosphorylation levels of inflammatory proteins regarding TLR4/MyD88/NF-κB/NLRP3 signaling pathway. In addition, TLR4-IN-C34 reduced ROS production in BV2 cells after LPS treatment. In conclusion, our findings suggest that anti-neuroinflammatory activity of TLR4-IN-C34 may be interrelated to the inhibition of TLR4/MyD88/NF-κB/NLRP3 signaling pathway and reduction of ROS generation.
TLR4 信号被脂多糖（LPS）激活，参与中枢神经系统（CNS）疾病的病理过程，抑制 TLR4 信号可能成为一种有效的治疗方法。TLR4-IN-C34 是一种 TLR4 抑制剂，有望成为具有抗神经炎症反应的候选化合物。本研究探讨了 TLR4-IN-C34 在 LPS 刺激的 BV2 小胶质细胞中对神经炎症的影响及可能的机制。结果表明，TLR4-IN-C34 降低了 LPS 刺激的 BV2 细胞上清液中促炎因子和趋化因子的水平，包括 NO、TNF-α、IL-1β、IL-6 和 MCP-1。进一步的研究表明，TLR4-IN-C34 抑制了 TLR4/MyD88/NF-κB/NLRP3 信号通路中炎症蛋白的表达或磷酸化水平。此外，TLR4-IN-C34 减少了 LPS 处理后 BV2 细胞中 ROS 的产生。综上所述，我们的研究结果表明，TLR4-IN-C34 的抗炎活性可能与抑制 TLR4/MyD88/NF-κB/NLRP3 信号通路和减少 ROS 生成有关。
