Year: 2025
Type: article
Abstract: Backgrounds: HIV-associated neurocognitive disorders (HAND) are the common complications in the central nervous system (CNS), mainly causing HIV dementia and leading to serious social economic load. HIV-1 gp120, the envelope protein of HIV-1, has been confirmed to be an important virulence factor of HAND, and the expression levels of pyroptosis-related genes in the brains of HIV-1 gp120 transgenic mice are significantly increased. Several studies have confirmed the broad neuroprotective potential of Kynurenic acid(KYNA) as a derivative of tryptophan metabolism. Our previous study found that tryptophan-fed mice had significantly increased KYNA levels in the brain and ameliorated HIV-1 gp120-induced neurological damage, but the mechanism is still unclear. In this study, we initially investigated the protective effect of KYNA against gp120-induced neuronal pyroptosis. Methods and materials: Sy5y-SH cells were used as the neuronal model in this study and grouped into control, LPS(2.5µg/L)+ATP(5mM), HIV-1 gp120(5nM), KYNA(25µM), HIV-1 gp120+KYNA(5µM), and HIV-1 gp120+KYNA(25µM) groups. The cells in the HIV-1 gp120 group were treated with gp120 (5nM) for 24h, and the cells in the ATP group were pretreated with ATP for 6h and LPS for 1h. After the treatment, the cells were lysed with RIPA, and the protein suspension was collected. Immunofluorescence was used to detect the expression level of ASC in each group, and Western blot was used to detect the expression of pyroptosis-related proteins in each group. Results: Immunofluorescence assay showed that KYNA treated did not affect ASC expression. HIV-1 gp120 and LPS+ATP significantly enhanced ASC expression compared control and KYNA-treated groups (P<0.05), and KYNA treatment inhibited ASC fluorescence intensity in a dose-dependent manner (P<0.05). In Western blot experiments, treatment with HIV-1 gp120 and LPS+ATP significantly increased GSDMD and NLRP3 expression in Sy5y-SH cells (P<0.05), and KYNA dose-dependently inhibited GSDMD and NLRP3 expression levels. In total, these results suggested that HIV-1 gp120 could cause neuronal pyroptosis, while KYNA could effectively reverse the changes in pyroptosis indicators. Discussion: HIV-1 gp120 is an important virulence factor in HIV-induced CNS injury, and our results indicate that HIV-1 gp120 can directly induce neuronal pyroptosis. In addition, the neuroprotective effect of KYNA has been widely confirmed, but there is still a lack of research on its protective mechanism against direct neuronal damage caused by infection. In this study, we initially investigated the protective effect of KYNA against HIV-1 gp120-induced neuronal pyroptosis. Conclusions: HIV-1 gp120 significantly increased the expression of ASC, GSDMD and NLRP3 in Sy5y-SH cells, while KYNA treatment significantly inhibited the above processes. (*Corresponding author: Hong Cao. Undergraduate Training Program for Innovation and Entrepreneurship of SMU, China, No.202012121216)
Authors: Dr Xuefeng Gao, Mr Wenchang Wang, Ms Yanjun Zhang, Ms Miaochun Chen, Prof Min Long, Mr. Xuefeng Gao
Language: English
Topic: HIV Research and Treatment
Subfield: Virology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,900
OpenAlex ID: W4408046629