HIV-1 subtype B Tat enhances NOTCH3 signaling in astrocytes to mediate oxidative stress, inflammatory response, and neuronal apoptosis.
J Neurovirol
; 29(4): 479-491, 2023 08.
Article
em En
| MEDLINE
| ID: mdl-37358698
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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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Infecções por HIV
/
HIV-1
/
Neuroblastoma
Limite:
Humans
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article