Institute of Pharmaceutical & Food Engineering, Shanxi University of Traditional Chinese Medicine, Jinzhong 030619, China; China Military Institute of Chinese Materia, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing 100039, China.
China Military Institute of Chinese Materia, The Fifth Medical Centre, Chinese PLA General Hospital, Beijing 100039, China.
Int Immunopharmacol. 2020 Apr;81:106271. doi: 10.1016/j.intimp.2020.106271. Epub 2020 Feb 12.
Glaucocalyxin A (GLA) is a bioactive ent-kauranoid diterpenoid derived from the herbal medicine, Rabdosia japonica var. glaucocalyx, and it has been reported to possess marked anti-inflammatory properties. However, the underlying mechanisms are not fully understood. Here, we reported that GLA dramatically inhibited canonical and non-canonical NLRP3 inflammasome activation induced by multiple agonists. In addition, GLA also blocked NLRC4 inflammasome activation but had no effect on AIM2 inflammasome. Furthermore, we found that GLA inhibited NLRP3 or NLRC4 agonists-induced ASC oligomerization, which is an upstream event of the inflammasomes assembly. Most importantly, administration of GLA significantly reduced lipopolysaccharide (LPS)-induced mortality in septic-shock mouse model. Additionally, GLA dose-dependently inhibited the production of interleukin (IL)-1β, but had no effect on NLRP3-independent TNF-α production induced by LPS in vivo. In conclusion, our study suggests that GLA alleviates LPS-induced septic shock and inflammation via inhibiting NLRP3 inflammasome activation and provides a promising candidate drug for the treatment of NLRP3-driven diseases.
滇黄芩苷 A（GLA）是一种来源于草药黄芩的生物活性贝壳杉烯二萜，据报道具有显著的抗炎特性。然而，其潜在机制尚不完全清楚。在这里，我们报道 GLA 可显著抑制多种激动剂诱导的经典和非经典 NLRP3 炎性小体激活。此外，GLA 还阻断 NLRC4 炎性小体的激活，但对 AIM2 炎性小体没有影响。此外，我们发现 GLA 抑制 NLRP3 或 NLRC4 激动剂诱导的 ASC 寡聚化，这是炎性小体组装的上游事件。最重要的是，GLA 的给药显著降低了脓毒症休克小鼠模型中的死亡率。此外，GLA 呈剂量依赖性地抑制白细胞介素（IL）-1β的产生，但对 LPS 诱导的 NLRP3 非依赖性 TNF-α产生没有影响。总之，我们的研究表明，GLA 通过抑制 NLRP3 炎性小体的激活来减轻 LPS 诱导的脓毒症休克和炎症，并为治疗 NLRP3 驱动的疾病提供了一种有前途的候选药物。
