期刊
INTERNATIONAL IMMUNOPHARMACOLOGY
卷 107, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.intimp.2022.108671
关键词
SIRT1; NLRP3 inflammasome; Pyroptosis; Mitophagy; IVDD
资金
- National Natural Science Foundation of China [82102556]
- Natural Science Foundationof Chongqing [cstc2019jcyj-msxmX0832, cstc2018jcyj-AX0059, cstc2018jcyj-AX0797]
Inflammatory stress of nucleus pulposus cells (NPCs) plays an important role in the pathogenesis of intervertebral disc degeneration (IVDD). Pyroptosis and NLRP3 inflammasome activation have been reported aggravating IVDD. SIRT1, by promoting PINK1/Parkin mediated mitophagy, alleviates IL-1 beta induced NLRP3 inflammasome activation in NPCs, thus may be a potential therapeutic target for IVDD.
Inflammatory stress of nucleus pulposus cells (NPCs) plays an important role in the pathogenesis of intervertebral disc degeneration (IVDD). Pyroptosis and NLRP3 inflammasome activation have been reported aggravating IVDD. SIRT1 is essential for mammalian cell survival and longevity by participating in various cellular processes. However, few studies analyzed the potential mechanism of SIRT1 in NLRP3-activated pyroptosis in NPCs. In this study, we confirmed that IL-1 beta could induce pyroptosis and NLRP3 inflammation activation, meanwhile, resulted in mitochondrial oxidative stress injury and dysfunction in NPCs. When the mitochondrial ROS was inhibited by Mito-Tempo, the pyroptosis and NLRP3 inflammation activation was also inhibited. SIRT1 overexpression could ameliorate IL-1 beta induced mitochondrial dysfunction and ROS accumulation, inhibit NLRP3 inflammasome activation by promoting PINK1/Parkin mediated mitophagy, however, these protective phenomena reversed by autophagy inhibitor 3-MA pretreatment. In vivo, SIRT1 agonist (SRT1720) treatment decreased the expression of NLRP3, p20, and IL-1 beta, increased the expression of PINK1 and LC3, delayed IVDD process in the rat model. Taken together, our results indicate that SIRT1 alleviates IL-1 beta induced NLRP3 inflammasome activation via mitophagy in NPCs, SIRT1 may be a potential therapeutic target to alleviate NLRP3-activated pyroptosis in the inflammatory stress related IVDD.
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