Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai, China.
Brain Pathol. 2011 May;21(3):279-97. doi: 10.1111/j.1750-3639.2010.00445.x. Epub 2010 Nov 3.
Chemokines are implicated in the neuroinflammation of several chronic neurodegenerative disorders. However, the precise role of chemokines in neurodegeneration is unknown. Thiamine deficiency (TD) causes abnormal oxidative metabolism in the brain as well as a well-defined microglia activation and neurodegeneration in the submedial thalamus nucleus (SmTN), which are common features of neurodegenerative diseases. We evaluated the role of chemokines in neurodegeneration and the underlying mechanism in a TD model. Among the chemokines examined, TD selectively induced neuronal expression of monocyte chemoattractant protein-1 (MCP-1) in the SmTN prior to microglia activation and neurodegeneration. The conditioned medium collected from TD-induced neurons caused microglia activation. With a neuron/microglia co-culture system, we showed that MCP-1-induced neurotoxicity required the presence of microglia, and exogenous MCP-1 was able to activate microglia and stimulated microglia to produce cytokines. A MCP-1 neutralizing antibody inhibited MCP-1-induced microglia activation and neuronal death in culture and in the thalamus. MCP-1 knockout mice were resistant to TD-induced neuronal death in SmTN. TD selectively induced the accumulation of reactive oxygen species in neurons, and antioxidants blocked TD-induced MCP-1 expression. Together, our results indicated an induction of neuronal MCP-1 during mild impairment of oxidative metabolism caused by microglia recruitment/activation, which exacerbated neurodegeneration.
趋化因子参与了几种慢性神经退行性疾病的神经炎症。然而，趋化因子在神经退行性变中的确切作用尚不清楚。硫胺素缺乏症（TD）会导致大脑异常氧化代谢，以及明确的小胶质细胞激活和丘脑中部核（SmTN）的神经退行性变，这些都是神经退行性疾病的共同特征。我们在 TD 模型中评估了趋化因子在神经退行性变中的作用及其潜在机制。在所检查的趋化因子中，TD 选择性地诱导 SmTN 中的神经元表达单核细胞趋化蛋白-1（MCP-1），然后是小胶质细胞激活和神经退行性变。从 TD 诱导的神经元中收集的条件培养基引起小胶质细胞激活。在神经元/小胶质细胞共培养系统中，我们表明 MCP-1 诱导的神经毒性需要小胶质细胞的存在，外源性 MCP-1 能够激活小胶质细胞并刺激小胶质细胞产生细胞因子。MCP-1 中和抗体抑制了培养物中和丘脑中的 MCP-1 诱导的小胶质细胞激活和神经元死亡。MCP-1 敲除小鼠对 SmTN 中 TD 诱导的神经元死亡具有抗性。TD 选择性地诱导神经元中活性氧的积累，抗氧化剂阻止了 TD 诱导的 MCP-1 表达。总之，我们的结果表明，在小胶质细胞募集/激活引起的氧化代谢轻度损伤期间，神经元中 MCP-1 的积累加剧了神经退行性变。
