HIV protease inhibitor attenuated astrocyte autophagy involvement in inflammation via p38 MAPK pathway
HIV protease inhibitor attenuated astrocyte autophagy involvement in inflammation via p38 MAPK pathway
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HIV蛋白酶抑制剂通过p38 MAPK途径减弱星形胶质细胞自噬参与炎症
DOI：
10.1016/j.antiviral.2022.105463
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发表时间：
2022
影响因子：
7.6
通讯作者：
Yulin Zhang
中科院分区：
文献类型：
--
作者：
Xue Chen;Wei Ding;Xiao Cui;Jiaqi Wei;Yang Zhang;Tong Zhang;Yulin Zhang
艾滋病毒相关的神经认知障碍（HAND）在艾滋病毒感染者中普遍存在，尽管使用抗逆转录病毒治疗（ART）。尽管已经提出了几个危险因素与HAND有关，但已经做出了大量努力来探索ART对HAND的神经毒性作用。HIV蛋白酶抑制剂（PI）是ART的重要成分，在体内外均具有神经毒性，可促进HAND的发生。然而，PI相关神经毒性的发病机制仍不清楚。在此，我们探讨PI治疗是否是HAND的潜在致病因素，并阐明其潜在机制。本研究以U87细胞为研究对象，研究了不同浓度的PI，包括洛匹那韦（LPV）、利托那韦（RTV）、地瑞那韦（darunavir）、茚地那韦（indinavir）和沙奎那韦（saquinavir），发现LPV、LPV/RTV和沙奎那韦（saquinavir）均能抑制U87细胞的自噬，Western blot结果显示，P62蛋白表达显著升高，LC 3 II/LC 3 I水平降低。此外，比较转录组学揭示了炎症反应的参与。在暴露于LPV的U87细胞的生理活动中，差异基因显著富集在.p38 MAPK信号通路中。本研究采用液相芯片技术、qRT-PCR、Elisa和western blot等方法验证了RNA测序的结果，提示LPV诱导了炎症反应，p38 MAPK通路参与了这一过程。总的来说，我们证明PI通过p38 MAPK途径减弱了炎症中星形胶质细胞自噬的参与，为HAND的机制提供了新的见解。
HIV-associated neurocognitive disorder (HAND) is prevalent in people living with HIV, despite the use of antiretroviral therapy (ART). Although several risk factors have been proposed to be related to HAND, substantial .effort has been made to explore the neurotoxic effects of ART on HAND. HIV protease inhibitor (PI), an essential .component of ART, has neurotoxicity in vivo and in vitro, which can contribute to the development of HAND. .However, the pathogenesis of PI-associated neurotoxicity remains unclear. Here, we explored whether PI .treatment is a potential pathogenic factor for HAND and elucidated its potential mechanisms. In our study, U87 .cells were exposed to PIs, including lopinavir (LPV), ritonavir (RTV), darunavir, indinavir, and saquinavir at .different concentrations, we found that LPV, LPV/RTV, and saquinavir attenuated autophagy in U87 cells, the .results of Western blot showed that the expression of p62 dramatically was elevated and the level of LC3II/LC3I .was decreased. Moreover, comparative transcriptomics revealed the involvement of the inflammatory response .in the physiological activities of U87 cells exposed to LPV, with differential genes significantly enriched in the .p38 MAPK signaling pathway. In the following study, we verified the results from RNA-sequence using the liquid .chip technique, qRT-PCR, Elisa, and western blots, which suggested that LPV induced inflammatory response and .the p38 MAPK pathway was involved in this process. Collectively, we demonstrated that PIs attenuated the .involvement of astrocyte autophagy in inflammation via the p38 MAPK pathway, providing new insights into the .mechanism of HAND.