Abstract
Fatty acid-binding proteins (FABPs) are relevant to multiple neurodegenerative diseases. However, the roles and mechanisms of FABPs in HIV-associated neurocognitive disorder (HAND) remain yet unclear. In this study, cultured BV-2 microglial cells and HT-22 neuronal cells were used for in vitro experiments and HAND mouse models were constructed through intracerebroventricular injection of lentiviral vectors for in vivo experiments. FABP expression was determined using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot. The interrelationship between Fabp4 and NF-κB signaling was investigated using chromatin immunoprecipitation, qRT-PCR, and Western blot. The role of Fabp4 in regulating inflammatory response was determined using qRT-PCR, enzyme-linked immunosorbent assay, Western blot, and immunofluorescence staining. Cell viability and apoptosis were analyzed using cell counting kit-8 assay and flow cytometry assay, respectively. Our results suggested an upregulation of Fabp4 expression in the presence of Tat. Tat-induced Fabp4 expression was directly regulated by NF-κB p65, followed by, Fabp4 facilitating Tat-activated NF-κB signaling pathway. We also observed that Fabp4 knockdown in microglial cells significantly suppressed inflammatory response and neuronal apoptosis both in vitro and in vivo. In conclusion, the presence of Tat in microglial cells results in Fabp4 and NF-κB to form a positive feedback loop leading to exacerbate inflammatory response and neuronal apoptosis.
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Funding
This study was supported by Doctoral research start-up fund of Yan'an University (YDBK2021-16), Nantong Science and Technology Project (JC2021001) and Scientific Research Project of Health Commission of Nantong (QB2020001, QB2020011).
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Lin Gao and Duo Cao designed the study and wrote the paper. Xiaodan Zhou and Shuhui Zhou performed the research. Jian Tao and Yanan Gao analyzed data. Gaoqiang Meng revised the paper. All co-authors have reviewed and approved of the article before submission.
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Highlights
• HIV-1 Tat promotes Fabp4 expression via NF-κB signaling pathway in microglia.
• Fabp4 mediates HIV-1 Tat-induced activation of NF-κB signaling.
• Knockdown of Fabp4 suppresses microglial inflammation and displays a neuroprotective effect against HIV-1 Tat.
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Zhou, X., Zhou, S., Tao, J. et al. HIV-1 Tat drives the Fabp4/NF-κB feedback loop in microglia to mediate inflammatory response and neuronal apoptosis. J. Neurovirol. 28, 483–496 (2022). https://doi.org/10.1007/s13365-022-01094-z
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DOI: https://doi.org/10.1007/s13365-022-01094-z