HIV-1 subtype B Tat enhances NOTCH3 signaling in astrocytes to mediate oxidative stress, inflammatory response and neuronal apoptosis

NOTCH receptors are relevant tomultiple 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 Tat expression in HEB astroglial cells. Moreover, subtype B Tat, rather than subtype C Tat interacted with the extracellular domain of NOTCH3 receptor, thus activating NOTCH3 signaling. Downregulation of NOTCH3 attenuated Tat-induced oxidative stress and reactive oxygen species generation. In addition, we demonstrated that NOTCH3 signaling facilitated 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 astrocytes-mediated Tat neurotoxicity. Taken together, our study clarifies the potential role of NOTCH3 in Tat-induced oxidative stress and inflammatory response in astrocytes, which could be a novel therapeutic target for relief of HAND.