Atorvastatin inhibited TNF-α induced matrix degradation in rat nucleus pulposus cells by suppressing NLRP3 inflammasome activity and inducing autophagy through NF-κB signaling
Atorvastatin inhibited TNF-α induced matrix degradation in rat nucleus pulposus cells by suppressing NLRP3 inflammasome activity and inducing autophagy through NF-κB signaling
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DOI：
10.1080/15384101.2021.1973707
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发表时间：
2021-09-10
期刊：
影响因子：
4.3
通讯作者：
Ye, Wei
中科院分区：
文献类型：
--
作者：
Chen, Jiancong;Yan, Jiansen;Ye, Wei
椎间盘退变（IDD）是腰痛（LBP）的主要原因之一。它是由髓核细胞内细胞外基质（ECM）成分的降解和合成不平衡引起的。阿托伐他汀是一种HMG-CoA还原酶抑制剂，在许多疾病中起着至关重要的作用，如心血管疾病和骨关节炎。然而，阿托伐他汀对缺乏症的影响尚不清楚。在此，我们证明了阿托伐他汀影响tnf - α诱导的基质降解，并证明了tnf - α调节大鼠NP细胞基质代谢的机制。采用Real-time PCR、western blotting和免疫荧光染色检测相关基因mRNA和蛋白表达情况。采用mRFP-GFP-LC3腺病毒质粒转染和透射电镜（TEM）检测细胞自噬。利用NLRP3抑制剂和含有shRNA-NLRP3的慢病毒载体，研究NLRP3对自噬通量和nf - κ B信号通路的影响。结果显示，阿托伐他汀可能通过抑制NLRP3炎性体活性和诱导自噬通量来抑制tnf - α诱导的基质降解。此外，阿托伐他汀抑制tnf - α诱导的NF-kappa B信号传导。NF-kappa B信号抑制抑制NLRP3炎性小体活性，NLRP3抑制抑制tnf - α诱导的NF-kappa B信号激活。在tnf - α存在下，NLRP3抑制或NLRP3敲低诱导自噬通量。综上所述，本研究表明阿托伐他汀可能抑制tnf - α诱导的基质降解，并进一步揭示了NLRP3炎症小体活性、自噬和nf - κ B信号传导之间的串扰。
Intervertebral disc degeneration (IDD) is one of the main causes of lower back pain (LBP). It results from an imbalance between the degradation and synthesis of extracellular matrix (ECM) components in nucleus pulposus (NP) cells. Atorvastatin, an HMG-CoA reductase inhibitor, plays a vital role in many diseases, such as cardiovascular disease and osteoarthritis. However, the effect of atorvastatin on IDD is unclear. Herein, we demonstrated that atorvastatin affects matrix degradation induced by TNF-alpha and demonstrated the mechanism by which TNF-alpha modulates matrix metabolism in rat NP cells. Real-time PCR, western blotting and immunofluorescence staining were performed to detect the mRNA and protein expression of related genes. mRFP-GFP-LC3 adenovirus plasmid transfection and transmission electron microscopy (TEM) were used to detect cell autophagy. NLRP3 inhibitor and lentiviral vectors containing shRNA-NLRP3 were used to show the effect of NLRP3 on autophagic flux and the NF-kappa B signaling pathway. The results revealed that atorvastatin might suppress matrix degradation induced by TNF-alpha by suppressing NLRP3 inflammasome activity and inducing autophagic flux. Moreover, atorvastatin suppressed NF-kappa B signaling induced by TNF-alpha. NF-kappa B signaling inhibition suppressed NLRP3 inflammasome activity, and NLRP3 inhibition suppressed NF-kappa B signaling activation induced by TNF-alpha. NLRP3 inhibition or NLRP3 knockdown induced autophagic flux in the presence of TNF-alpha. Overall, the present study demonstrated that atorvastatin might suppress matrix degradation induced by TNF-alpha and further revealed the crosstalk among NLRP3 inflammasome activity, autophagy and NF-kappa B signaling.