Muscone eliminates sepsis through promotes mitochondrial autophagy during NLRP3 inflammasome activation

Musk from male deer (genus Moschus) is used in traditional Chinese medicine for thousands of years due to its anti-inflammatory effects. Muscone, as the main substance of musk, is used in chronic inflammation after myocardial infarction and susceptibility to ventricular arrhythmia by means of controlling inflammation. And previous studies reveal that muscone has a bioactivity of anti-NLRP3 inflammasome activation especially. However, how muscone suppress NLRP3 inflammasome activation is still unclear. In the current study, LPS-primed peritoneal macrophages were employed for validation of muscone suppressing NLRP3 inflammasome activation in vitro. Secondly, we found the occurrence of mitophagy in muscone treatment group by means of RNA-seq. Thirdly, we conducted fluorescence co-localization and electron microscopic analysis to verify whether muscone promote mitophagy during NLRP3 inflammasome activation. Next, we used LPS-induced sepsis mice to examine muscone promoting mitophagy in vivo. Finally, we further inquired the target of muscone promoting mitophagy with help of docking tools. We found that muscone suppressed NLRP3 inflammasome activation both in priming and activation stages in vitro. For priming stage, muscone downregulated the production of NLRP3 and pro-IL-1β with inhibiting NF-κB signaling pathway. For activation stage, muscone disturbed assembly of NLRP3 inflammasome with suppressing ASC oligomerization, interaction of ASC-pro-caspase1. Based on RNA-seq data, we speculated that muscone may promote mitophagy during NLRP3 inflammasome activation. Then we found evidences that muscone promoted mitophagy both in NLRP3 inflammasome activated macrophages and LPS-induced sepsis mice. Finally, molecular docking results displayed that muscone had strong hydrophobic interaction with TSPO, which may one of reasons for muscone promoting mitophagy. Muscone promoted mitophagy both in NLRP3 inflammasome activated macrophages and LPS-induced sepsis mice. Muscone shows a superb potential as a NLRP3 inflammasome inhibitor and a mitophagy agonist for further optimization of structure and application in clinic in trap future.