SIRT1 alleviates IL-1β induced nucleus pulposus cells pyroptosis via mitophagy in intervertebral disc degeneration

Mar 19, 2022International immunopharmacology

SIRT1 reduces cell death caused by inflammation in spinal disc degeneration by clearing damaged mitochondria

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Abstract

SIRT1 agonist treatment decreased the expression of NLRP3, p20, and IL-1β in a rat model of intervertebral disc degeneration.

Inflammatory stress of nucleus pulposus cells is associated with intervertebral disc degeneration.
IL-1β induces pyroptosis and activates the NLRP3 inflammasome, leading to mitochondrial oxidative stress in nucleus pulposus cells.
Inhibition of mitochondrial reactive oxygen species reduces pyroptosis and NLRP3 activation.
SIRT1 overexpression improves mitochondrial function and reduces inflammatory responses by promoting specific cellular cleanup processes.
In vivo results suggest SIRT1 may help delay the progression of intervertebral disc degeneration.

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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-1β 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-1β 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-1β, increased the expression of PINK1 and LC3, delayed IVDD process in the rat model. Taken together, our results indicate that SIRT1 alleviates IL-1β 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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SIRT1 alleviates IL-1β induced nucleus pulposus cells pyroptosis via mitophagy in intervertebral disc degeneration

Abstract

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