Leojaponin inhibits NLRP3 inflammasome activation through restoration of autophagy via upregulating RAPTOR phosphorylation,Journal of Ethnopharmacology

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Leojaponin inhibits NLRP3 inflammasome activation through restoration of autophagy via upregulating RAPTOR phosphorylation
Journal of Ethnopharmacology ( IF 4.8 ) Pub Date : 2021-06-09 , DOI: 10.1016/j.jep.2021.114322
Xing-Jie Zhang ₁ , Kun Shang ₁ , Yu-Kun Pu ₁ , Qi Wang ₁ , Ting-Ting Wang ₁ , Yan Zou ₁ , Yong-Mei Wang ₁ , Yao-Jun Xu ₁ , Xiao-Li Li ₁ , Rui-Han Zhang ₁ , Wei-Lie Xiao ₁

Affiliation

Ethnopharmacological relevance

Duan Teng Yimu decoction is a Chinese herbal medicine compound with proven therapeutic effects on inflammasome-related diseases, such as rheumatoid arthritis. This decoction consists of three Chinese herbal medicines, including Leonurus japonicus (L. japonicus), which promotes the blood circulation and exhibits detumescence activity, traditionally curing gynecologic and inflammasome diseases.

Aim of the study

To explore the anti-inflammasome activity and the underlying mechanisms of action of the compounds from L. japonicus.

Materials and Methods

A series of compounds were isolated from L. japonicus. Their anti-inflammasome activities were evaluated in macrophages that were co-stimulated by lipopolysaccharide (LPS) and NLRP3 inflammasome inducers. NLRP3 inflammasome formation and apoptosis speck like containing a CARD (ASC) oligomerization were evaluated by immunofluorescent microscopy and Western blot analysis. The regulation of autophagy after treatment of this compound was also evaluated. Lastly, in vivo activity of Leojaponin was analyzed in a rat acute gouty arthritis model.

Results

Here we show that Leojaponin, a diterpenoid compound from L. japonicus, suppressed lactate dehydrogenase and IL-1β release in Nigericin-stimulated macrophages in a pyroptosis model. Leojaponin inhibits NLRP3 inflammasome activation in both J774A.1 cells and bone marrow-derived macrophages in a dose dependent manner. Moreover, Leojaponin suppressed NLRP3-mediated ASC specks formation and ASC oligomerization. These activities of Leojaponin depend on restoration of autophagy via promoting RAPTOR phosphorylation. Furthermore, Leojaponin ameliorated monosodium urate (MSU)-induced acute gouty arthritis in vivo.

Conclusion

Our findings suggest that Leojaponin inhibits NLRP3 inflammasome activation through enhancing autophagy via RAPTOR phosphorylation, thereby highlighting Leojaponin as a potent drug for inflammasome-related diseases.

中文翻译：

Leojaponin 通过上调 RAPTOR 磷酸化恢复自噬来抑制 NLRP3 炎症小体激活

民族药理学相关性

段藤益母汤是一种中草药复方，对类风湿性关节炎等炎症小体相关疾病具有治疗作用。此汤由三种中草药组成，包括益母草（L. japonicus），具有活血化瘀作用，传统上治疗妇科疾病和炎症性疾病。

研究目的

探讨日本刺参化合物的抗炎活性和潜在作用机制。

材料和方法

从日本海参中分离出一系列化合物。在脂多糖 (LPS) 和 NLRP3 炎症小体诱导剂共同刺激的巨噬细胞中评估了它们的抗炎活性。通过免疫荧光显微镜和蛋白质印迹分析评估 NLRP3 炎性体形成和凋亡斑点样含有 CARD (ASC) 寡聚化。还评估了该化合物处理后的自噬调节。最后，在大鼠急性痛风性关节炎模型中分析了 Leojaponin 的体内活性。

结果

在这里，我们展示了 Leojaponin，一种来自L. japonicus的二萜化合物，在细胞焦亡模型中抑制了尼日利亚菌素刺激的巨噬细胞中乳酸脱氢酶和 IL-1β 的释放。Leojaponin 以剂量依赖性方式抑制 J774A.1 细胞和骨髓来源的巨噬细胞中的 NLRP3 炎症小体活化。此外，Leojaponin 抑制 NLRP3 介导的 ASC 斑点形成和 ASC 寡聚化。Leojaponin 的这些活性依赖于通过促进 RAPTOR 磷酸化来恢复自噬。此外，Leojaponin在体内改善了单钠尿酸盐 (MSU) 诱导的急性痛风性关节炎。