Glaucocalyxin A alleviates LPS-mediated septic shock and inflammation via inhibiting NLRP3 inflammasome activation
Glaucocalyxin A alleviates LPS-mediated septic shock and inflammation via inhibiting NLRP3 inflammasome activation
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DOI：
10.1016/j.intimp.2020.106271
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发表时间：
2020-04-01
影响因子：
5.6
通讯作者：
Bai, Zhaofang
中科院分区：
文献类型：
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作者：
Hou, Xiaorong;Xu, Guang;Bai, Zhaofang
蓝萼甲素（GLA）是一种从草药冬凌草（Rabdosia japonica var. glaucocalyx）中提取的具有生物活性的对映-贝壳杉烷型二萜类化合物，据报道它具有显著的抗炎特性。然而，其潜在机制尚未完全清楚。在此，我们报道GLA显著抑制多种激动剂诱导的经典和非经典NLRP3炎症小体激活。此外，GLA还阻断NLRC4炎症小体激活，但对AIM2炎症小体无影响。进一步，我们发现GLA抑制NLRP3或NLRC4激动剂诱导的ASC寡聚化，这是炎症小体组装的上游事件。最重要的是，在脓毒症休克小鼠模型中，给予GLA显著降低脂多糖（LPS）诱导的死亡率。此外，GLA呈剂量依赖性地抑制白细胞介素（IL）-1β的产生，但对体内LPS诱导的不依赖NLRP3的肿瘤坏死因子-α（TNF -α）产生无影响。总之，我们的研究表明，GLA通过抑制NLRP3炎症小体激活缓解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景的候选药物。
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)-1 beta, but had no effect on NLRP3-independent TNF-alpha 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.