Quercetin Interrupts the SIRT3/ROS/NF-κB/SPI1 Feedback Loop to Ameliorate Microglia-Mediated HIV-1 Tat Neurotoxicity

Quercetin, a kind of flavonoids, has been implicated in multiple neurological diseases. Nevertheless, the functional roles and mechanisms of quercetin in HIV-associated neurocognitive disorders (HAND) remain unclear. HIV-1-encoded transactivator of transcription (Tat) is the major pathogenic factor for the progression of HAND. In the central nervous system, microglia-mediated Tat neurotoxicity is mainly comprised of inflammatory response, nitric oxide (NO) and excessive glutamate. In this study, we demonstrated that Tat-activated NF-κB p65 directly induce the release of IL-6 and TNF-α as well as NO production, while Tat promoted glutamate release via NF-κB/SPI1 pathway. Conversely, quercetin could upregulate SIRT3 expression to reduce reactive oxygen species (ROS) generation, thereby inhibiting NF-κB/SPI1 pathway and mitigating microglia-mediated Tat neurotoxicity. In addition, we also observed that quercetin alleviated neuronal apoptosis induced by the microglia-derived conditioned media in a SIRT3/ROS/NF-κB-dependent manner. Furthermore, Tat was found to downregulate SIRT3 expression via NF-κB/SPI1 pathway, which was reversed by quercetin in microglia. Thus, our data establish that quercetin disrupts the SIRT3/ROS/NF-κB/SPI1 feedback loop to attenuate microglia-mediated Tat neurotoxicity. Finally, in murine models, we recapitulated that administration of quercetin remarkably ameliorated Tat‑induced neuropathy and cognitive decline in vivo. Taken together, our study uncovers the neuroprotective roles of quercetin in the amelioration of microglia-mediated Tat neurotoxicity and highlights its potential as a therapeutic agent for the treatment of HAND.