Abstract
Methamphetamine (METH) and HIV-1 lead to oxidative stress and their combined effect increases the risk of HIV-associated neurocognitive disorder (HAND), which may be related to the synergistic ferroptotic impairment in microglia. Ferroptosis is a redox imbalance cell damage associated with iron overload that is linked to the pathogenic processes of METH and HIV-1. NRF2 is an antioxidant transcription factor that plays a protective role in METH and HIV-1-induced neurotoxicity, but its mechanism has not been fully elucidated. To explore the role of ferroptosis in METH abuse and HIV-1 infection and the potential role of NRF2 in this process, we conducted METH and HIV-1 Tat exposure models using the BV2 microglia cells. We found that METH and HIV-1 Tat reduced the expression of ferroptotic protein GPX4 and the cell viability and enhanced the expression of P53 and the level of ferrous iron, while the above indices were significantly improved with pretreatment of ferrostatin-1. In addition, NRF2 knockdown accelerated METH and HIV-1 Tat-induced BV2 cell ferroptosis accompanied by decreased expression of SLC7A11. On the contrary, NRF2 stimulation significantly increased the expression of SLC7A11 and attenuated ferroptosis in cells. In summary, our study indicates that METH and HIV-1 Tat synergistically cause BV2 cell ferroptosis, while NRF2 antagonizes BV2 cell ferroptotic damage induced by METH and HIV-1 Tat through regulation of SLC7A11. Overall, this study provides potential therapeutic strategies for the treatment of neurotoxicity caused by METH and HIV-1 Tat, providing a theoretical basis and new targets for the treatment of HIV-infected drug abusers.
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Abbreviations
- DMEM:
-
Dulbecco-modified Eagle medium
- DAPI:
-
4,6-Diamidino-2-phenylindole
- FBS:
-
Fetal bovine serum
- GPX4:
-
Recombinant glutathione peroxidase 4
- HIV-1 Tat:
-
Human immunodeficiency virus-1 transactivator of transcription
- HAND:
-
HIV-1-associated neurocognitive disorders
- KO:
-
Knockout
- METH:
-
Methamphetamine
- NFE2L2/NRF2:
-
Nuclear factor, erythroid-derived 2, like 2
- P53:
-
Cellular tumor antigen P53
- PBS:
-
Phosphate-buffered saline
- SFN:
-
Sulforaphane
- SLC7A11:
-
Solute carrier family 7 member 11
- TBS:
-
Tris-base-buffered saline
- TBST:
-
Tris-HCl buffered saline-Tween 20
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This work was supported by the National Nature Science Foundation of China (82160325, 82060382, and 81960340), the Yunnan Applied Basic Research Projects Joint Special Project (202201AY070001-020), and the Basic Research Program of Yunnan Province (202001AT070098).
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We acknowledge Lin S.C., Cheng H., Yang G.M., Wang C., Leung C.K., Zhang S.W., Tan Y., Zhang H.J., Wang H.W., Miao L., Li Y., and Huang Y. Z. for their contribution in literature searching, experimental validation, data analysis, and manuscript writing and acknowledge Li J., Zhang R.L., and Zeng X.F. for supervising the study design and the manuscript edition. All the authors approved the final version for publication.
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Shucheng Lin, Hao Cheng, Genmeng Yang, and Chan Wang have contributed equally to this work.
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Lin, S., Cheng, H., Yang, G. et al. NRF2 Antagonizes HIV-1 Tat and Methamphetamine-Induced BV2 Cell Ferroptosis by Regulating SLC7A11. Neurotox Res 41, 398–407 (2023). https://doi.org/10.1007/s12640-023-00645-4
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DOI: https://doi.org/10.1007/s12640-023-00645-4