Zhang Qifei, Tao Wenhua, Wang Jing, Qian Meijuan, Zhou Mingming, Gao Lin
Nantong Health College of Jiangsu Province, Nantong, 226001, People's Republic of China.
Department of Traditional Chinese Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, 212000, People's Republic of China.
J Neurovirol. 2025 Mar 26. doi: 10.1007/s13365-025-01249-8.
Oxidized low density lipoprotein receptor 1 (OLR1), a type II integral membrane glycoprotein, is involved in multiple neurological diseases. However, the roles and mechanisms of OLR1 in HIV-associated neurocognitive disorder (HAND) remain unclear. In the central nervous system, Transactivator of transcription (Tat) induces inflammatory response in microglia, thereby leading to neuronal apoptosis. In the present study, we demonstrated that OLR1 expression was upregulated during ectopic expression of Tat or soluble Tat stimulus in BV-2 microglial cells. Moreover, OLR1 signaling was proved to facilitate Tat-triggered inflammatory response and alleviated the microglia-derived conditioned media-mediated HT-22 neural cells apoptosis in a NF-κB-dependent manner. Conversely, Tat augmented OLR1 expression via NF-κB signaling pathway. Finally, in mouse models, we determined that silencing of OLR1 significantly ameliorated Tat‑induced neuroinflammation and hippocampal neuronal death. Taken together, our study clarifies the potential role of the OLR1/NF-κB feedback loop in Tat-induced microglial inflammatory response and neuronal apoptosis, which could be a novel therapeutic target for relief of HAND.
氧化型低密度脂蛋白受体1（OLR1）是一种II型整合膜糖蛋白，与多种神经系统疾病有关。然而，OLR1在HIV相关神经认知障碍（HAND）中的作用和机制仍不清楚。在中枢神经系统中，转录激活因子（Tat）可诱导小胶质细胞发生炎症反应，进而导致神经元凋亡。在本研究中，我们证明在BV-2小胶质细胞中异位表达Tat或给予可溶性Tat刺激时，OLR1的表达会上调。此外，还证实OLR1信号传导可促进Tat触发的炎症反应，并以NF-κB依赖的方式减轻小胶质细胞来源的条件培养基介导的HT-22神经细胞凋亡。相反，Tat通过NF-κB信号通路增加OLR1的表达。最后，在小鼠模型中，我们确定沉默OLR1可显著改善Tat诱导的神经炎症和海马神经元死亡。综上所述，我们的研究阐明了OLR1/NF-κB反馈环在Tat诱导的小胶质细胞炎症反应和神经元凋亡中的潜在作用，这可能是缓解HAND的一个新的治疗靶点。
