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TXNIP Regulates NLRP3 Inflammasome-Induced Pyroptosis Related to Aging via cAMP/PKA and PI3K/Akt Signaling Pathways

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Abstract

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.

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Data Availability

All datasets generated and analyzed during this study are available from the corresponding author upon reasonable request.

Abbreviations

NLRP3:

Nucleotide-binding oligomerization domain

LRR:

Leucine-rich repeat domain

PYD:

Pyrin domain

CARD:

Caspase recruitment domains

ASC:

Apoptosis-associated speck-like protein containing a CARD domain

TXNIP:

Thioredoxin-interacting protein

IL-1β:

Interleukin-1β

IL-18:

Interleukin-18

TRX:

Thioredoxin

VDUP-1:

Vitamin D3 upregulated protein-1

TBP-2:

Thioredoxin-binding protein-2

PI3K:

The phosphatidylinositol 3-kinase

Akt:

Protein kinase B

cAMP:

Cyclic adenosine monophosphate

PKA:

Protein kinase A

DMEM:

Dulbecco’s Modified Eagle’s Medium

FBS:

Fetal bovine serum

GSDMD-N:

Gasdermin-N domains

GSDMD-C:

Gasdermin-C domains

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Acknowledgements

We thank all members of Prof. Gong’s Lab for scientific advice and helpful discussions.

Funding

The study was supported by the National Natural Science Foundation of China (82372557), the Capital Funds for Health Improvement and Research (2022-1-2251), and the Natural Science Foundation of Bei**g (7222101).

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Author notes

  1. **aoshuang ** and Rong Zhang contributed equally.

Authors and Affiliations

  1. Bei**g Rehabilitation Hospital, Capital Medical University, Bei**g, China

    **aoshuang **, Yijia Chi, Ziman Zhu & Ruifeng Sun

  2. Bei**g Rehabilitation Medicine Academy, Capital Medical University, Bei**g, China

    **aoshuang **, Yijia Chi, Ziman Zhu & Ruifeng Sun

  3. The Second Clinical Medical College, Yunnan University of Chinese Medicine, Kunming, Yunnan, China

    Rong Zhang

  4. Department of Neurological Rehabilitation, Bei**g Rehabilitation Hospital, Capital Medical University, Bei**g, China

    Weijun Gong

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Contributions

Weijun Gong and **aoshuang ** conceived the project and designed the experiments. W. Gong supervised the experiments. **aoshuang **, Rong Zhang, Yijia Chi, Ziman Zhu, and Ruifeng Sun performed the experiments and data analysis. **aoshuang ** made the figures. Weijun Gong and **aoshuang ** wrote the paper.

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**, X., Zhang, R., Chi, Y. et al. TXNIP Regulates NLRP3 Inflammasome-Induced Pyroptosis Related to Aging via cAMP/PKA and PI3K/Akt Signaling Pathways. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-04089-5

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