Beijing Rehabilitation Hospital, Capital Medical University, Beijing, China.
Beijing Rehabilitation Medicine Academy, Capital Medical University, Beijing, China.
Mol Neurobiol. 2024 Oct;61(10):8051-8068. doi: 10.1007/s12035-024-04089-5. Epub 2024 Mar 9.
Aging is an inevitable natural process with time-dependent dysfunction and the occurrence of various diseases, which impose heavy burdens on individuals, families, and society. It has been reported that NLRP3 inflammasome-induced pyroptosis contributes significantly to age-related diseases and aging, while TXNIP is suggested to be involved in regulating pyroptosis mediated by NLRP3. However, the mechanism between TXNIP and NLRP3 inflammasome is still unclear. In this study, we used HT-22 cells to explore the effect of TXNIP on pyroptosis and its potential association with the aging. Also, we delved into the underlying mechanisms. Our findings revealed that TXNIP significantly augmented pyroptosis in HT-22 cells, primarily by enhancing the activation of the NLRP3 inflammasome and promoting the release of proinflammatory cytokines. Remarkably, as TXNIP levels increased, we observed a corresponding rise in the number of p16-positive cells, which is indicative of aging. Furthermore, we conducted experiments to modulate the improvement of TXNIP on NLRP3 inflammasome-induced pyroptosis, that is, the PI3K activator 740 Y-P and the PKA activator DC2797 inhibited the effect, while the PI3K inhibitor LY294002 and the PKA inhibitor H89 enhanced the effect. In conclusion, our study demonstrated that TXNIP regulates NLRP3 inflammasome-induced pyroptosis in HT-22 cells related to aging via the PI3K/Akt and cAMP/PKA pathways.
衰老是一个随着时间的推移而出现功能障碍和各种疾病的不可避免的自然过程，这给个人、家庭和社会带来了沉重的负担。据报道，NLRP3 炎性体诱导的细胞焦亡对与年龄相关的疾病和衰老有重要贡献，而 TXNIP 被认为参与调节 NLRP3 介导的细胞焦亡。然而，TXNIP 和 NLRP3 炎性体之间的机制尚不清楚。在这项研究中，我们使用 HT-22 细胞来探索 TXNIP 对细胞焦亡的影响及其与衰老的潜在关联。此外，我们还探讨了潜在的机制。我们的研究结果表明，TXNIP 显著增强了 HT-22 细胞中的细胞焦亡，主要是通过增强 NLRP3 炎性体的激活并促进促炎细胞因子的释放。值得注意的是，随着 TXNIP 水平的升高，我们观察到 p16 阳性细胞的数量相应增加，这表明细胞衰老。此外，我们进行了实验来调节 TXNIP 对 NLRP3 炎性体诱导的细胞焦亡的改善作用，即 PI3K 激活剂 740 Y-P 和 PKA 激活剂 DC2797 抑制了这种作用，而 PI3K 抑制剂 LY294002 和 PKA 抑制剂 H89 增强了这种作用。总之，我们的研究表明，TXNIP 通过 PI3K/Akt 和 cAMP/PKA 途径调节 HT-22 细胞中与衰老相关的 NLRP3 炎性体诱导的细胞焦亡。
