Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
Neurochem Int. 2012 Dec;61(7):1021-35. doi: 10.1016/j.neuint.2012.07.019. Epub 2012 Jul 27.
Chronic neurodegeneration is in part caused by a vicious cycle of persistent microglial activation and progressive neuronal cell loss. However, the driving force behind this cycle remains poorly understood. In this study, we used medium conditioned by necrotic differentiated-PC12 cells to confirm that damaged neurons can release soluble injury signals, including heat shock protein 60 (HSP60), to efficiently promote the neurotoxic cycle involving microglia. Since lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) has previously been identified as a novel receptor for HSP60, we hypothesize that LOX-1 through binding to extracellular HSP60 promotes microglia-mediated neuroinflammation. In this study, we observed that LOX-1 expression is induced upon toxic microglial activation, and discovered that LOX-1 is necessary in microglia for sensing soluble neuronal injury signal(s) in the conditioned medium to induce generation of pro-inflammatory mediators (IL-1β, TNF-α, NO and ROS) that promote neurotoxicity. Employing a unique eukaryotic HSP60-overexpression method, we further demonstrated that extracellular HSP60 acts on microglial LOX-1 to boost the production of pro-inflammatory factors (IL-1β, NO and ROS) in microglia and to propagate neuronal damage. These results indicate that LOX-1 is essential in microglia for promoting an inflammatory response in the presence of soluble neuronal-injury signals such as extracellular HSP60, thereby linking neuroinflammation and neurotoxicity.
慢性神经退行性变部分是由持续的小胶质细胞激活和进行性神经元细胞丢失的恶性循环引起的。然而，这个循环背后的驱动力仍知之甚少。在这项研究中，我们使用由坏死分化的 PC12 细胞条件培养基来证实受损神经元可以释放可溶性损伤信号，包括热休克蛋白 60（HSP60），以有效地促进涉及小胶质细胞的神经毒性循环。由于凝集素样氧化型低密度脂蛋白受体-1（LOX-1）先前已被鉴定为 HSP60 的新型受体，我们假设 LOX-1 通过与细胞外 HSP60 结合来促进小胶质细胞介导的神经炎症。在这项研究中，我们观察到 LOX-1 的表达在有毒的小胶质细胞激活时被诱导，并且发现 LOX-1 在小胶质细胞中对于感知条件培养基中的可溶性神经元损伤信号以诱导促炎介质（IL-1β、TNF-α、NO 和 ROS）的产生是必需的，这些介质促进神经毒性。采用独特的真核 HSP60 过表达方法，我们进一步证明细胞外 HSP60 作用于小胶质细胞的 LOX-1，以增强小胶质细胞中促炎因子（IL-1β、NO 和 ROS）的产生，并促进神经元损伤。这些结果表明，LOX-1 在小胶质细胞中对于促进炎症反应是必不可少的，这种炎症反应存在于细胞外 HSP60 等可溶性神经元损伤信号中，从而将神经炎症和神经毒性联系起来。
