Wang Huili, Zuo Qin, Li Xinyi, Liu Yuanyuan, Gan Limeng, Wang Linlin, Rao Yin, Pan Rui, Dong Jun
Department of Pathophysiology, Key Laboratory of the State Administration of Traditional Chinese Medicine, Medical College of Jinan University, Guangzhou, Guangdong Province, China.
Department of Orthopedics, The First Affiliated Hospital, Medical College of Jinan University, Guangzhou, Guangdong Province, China.
Inflammation. 2024 Dec 28. doi: 10.1007/s10753-024-02229-6.
The main pathogenic mechanism of HIV-associated neurocognitive disorders (HAND) is neuronal apoptosis induced by inflammatory mediators, in which microglial inflammation plays a crucial role. However, the exact pathogenic mechanism remains unclear. Previous studies have shown that the HIV-1 gp120 V3 loop can trigger inflammation in CHME-5 microglia. p62 is a post-translational modified multidomain protein that is involved in the regulation of autophagy and is closely related to neuroinflammation. In this study, we found that p62 knockout down-regulated the expression of MCP-1, IL-6 and COX-2, and improved the inflammation of HIV-1 gp120 V3 loop induced microglia, while overexpression of p62 up-regulated the expression of MCP-1, IL-6 and COX-2, and promoted the inflammation of microglia. In addition, protein kinase C (PKC) knockout down-regulated the expression of MCP-1, IL-6 and COX-2 and inhibited the activation of IKK/ NF-κ B pathway, while tumor necrosis factor receptor-associated factor 6 (TRAF6) knockout had no significant effect on the expression of MCP-1, IL-6 and COX-2. Co-immunoprecipitation showed that p62 was bound and interacted with PKC. Inhibition of IKK/ NF-κ B pathway can down-regulate the expression of MCP-1, IL-6 and COX-2, and improve the inflammatory response of microglia. Our research further found that inhibition of IKK/ NF-κ B can decrease the expression of Caspase-3 and reduce the apoptosis of neurons in the co-culture of CHME-5 microglia and primary mouse neurons. The results of this study suggest that HIV-1 gp120 V3 loop induced CHME-5 microglial inflammation may be activated by the direct binding of p62 and PKC through the IKK/ NF-κ B signaling pathway, and these findings provide an important reference for the prevention and treatment of HAND.
人类免疫缺陷病毒相关神经认知障碍（HAND）的主要致病机制是炎症介质诱导的神经元凋亡，其中小胶质细胞炎症起关键作用。然而，确切的致病机制仍不清楚。先前的研究表明，HIV-1 gp120 V3环可引发CHME-5小胶质细胞炎症。p62是一种翻译后修饰的多结构域蛋白，参与自噬调节，与神经炎症密切相关。在本研究中，我们发现p62基因敲除下调了MCP-1、IL-6和COX-2的表达，并改善了HIV-1 gp120 V3环诱导的小胶质细胞炎症，而p62过表达上调了MCP-1、IL-6和COX-2的表达，并促进了小胶质细胞炎症。此外，蛋白激酶C（PKC）基因敲除下调了MCP-1、IL-6和COX-2的表达，并抑制了IKK/NF-κB通路的激活，而肿瘤坏死因子受体相关因子6（TRAF6）基因敲除对MCP-1、IL-6和COX-2的表达无显著影响。免疫共沉淀显示p62与PKC结合并相互作用。抑制IKK/NF-κB通路可下调MCP-1、IL-6和COX-2的表达，并改善小胶质细胞的炎症反应。我们的研究进一步发现，抑制IKK/NF-κB可降低Caspase-3的表达，并减少CHME-5小胶质细胞与原代小鼠神经元共培养中神经元的凋亡。本研究结果表明，HIV-1 gp120 V3环诱导的CHME-5小胶质细胞炎症可能通过p62与PKC的直接结合经IKK/NF-κB信号通路激活，这些发现为HAND的防治提供了重要参考。
