Abstract
NOTCH receptors are relevant to multiple neurodegenerative diseases. However, the roles and mechanisms of NOTCH receptors in HIV-associated neurocognitive disorder (HAND) remain largely unclear. Transactivator of transcription (Tat) induces oxidative stress and inflammatory response in astrocytes, thereby leading to neuronal apoptosis in the central nervous system. We determined that NOTCH3 expression was upregulated during subtype B or C Tat expression in HEB astroglial cells. Moreover, bioinformatics analysis of the Gene Expression Omnibus (GEO) dataset revealed that NOTCH3 mRNA expression in the frontal cortex tissues of HIV encephalitis patients was higher than that of HIV control patients. Of note, subtype B Tat, rather than subtype C Tat, interacted with the extracellular domain of the NOTCH3 receptor, thus activating NOTCH3 signaling. Downregulation of NOTCH3 attenuated subtype B Tat-induced oxidative stress and reactive oxygen species generation. In addition, we demonstrated that NOTCH3 signaling facilitated subtype B Tat-activated NF-κB signaling pathway, thereby mediating pro-inflammatory cytokines IL-6 and TNF-α production. Furthermore, downregulation of NOTCH3 in HEB astroglial cells protected SH-SY5Y neuronal cells from astrocyte-mediated subtype B Tat neurotoxicity. Taken together, our study clarifies the potential role of NOTCH3 in subtype B Tat-induced oxidative stress and inflammatory response in astrocytes, which could be a novel therapeutic target for the relief of HAND.
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Data availability
The data that support the findings of this study are available on request from the corresponding authors, upon reasonable request.
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Funding
This research received the support of Jiangsu Provincial Medical Key Discipline (Laboratory) Cultivation Unit (JSDW202249), Scientific Research Innovation Team of Kangda College of Nanjing Medical University (KD2022KYCXTD005), National Natural Science Foundation of China (81904166), Nantong Science and Technology Project (JC2021001), Scientific Research Project of Health Commission of Nantong (MS2022025), and Nantong First People's Hospital High-level Science and Technology Project Cultivation Fund (YPYJJYB002).
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Lin Gao and Hongbin Liu designed the study. Lin Gao and Weixi Sun performed the research. Dongmei Zhang, Yanxing Shang, and Li Li analyzed data. Lei Zhang wrote the paper. Wenhua Tao revised the paper. All co-authors have reviewed and approved of the article before submission.
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Highlights
• HIV-1 subtype B Tat promotes NOTCH3 expression and NOTCH3 signaling activation in astrocytes.
• Knockdown of NOTCH3 suppresses HIV-1 subtype B Tat-induced oxidative stress and inflammatory response in astrocytes.
• Knockdown of NOTCH3 in astrocytes displays a neuroprotective effect against HIV-1 subtype B Tat.
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Gao, L., Sun, W., Zhang, D. et al. HIV-1 subtype B Tat enhances NOTCH3 signaling in astrocytes to mediate oxidative stress, inflammatory response, and neuronal apoptosis. J. Neurovirol. 29, 479–491 (2023). https://doi.org/10.1007/s13365-023-01151-1
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DOI: https://doi.org/10.1007/s13365-023-01151-1