Department of Pathology, University of California, San Francisco, CA 94143.
Proc Natl Acad Sci U S A. 2013 Nov 5;110(45):18291-6. doi: 10.1073/pnas.1208764110. Epub 2013 Oct 21.
Nuclear factor erythroid 2-related factor 2 (Nrf2), the transcriptional master regulator of the stress-induced antioxidant response, plays a key role in neuronal resistance to oxidative stress and glutamate-induced excitotoxicity. Nrf2-mediated neuroprotection is primarily conferred by astrocytes both in vitro and in vivo, but little is known about physiologic signals that regulate neuronal and astrocytic Nrf2 signaling. Here, we report that activity of the Nrf2 pathway in the brain is fine-tuned through a regulatory loop between neurons and astrocytes: elevated neuronal activity leads to secretion of glutamate and other soluble factors, which activate the astrocytic Nrf2 pathway through a signaling cascade that involves group I metabotropic glutamate receptors and intracellular Ca(2+). Therefore, regulation of endogenous antioxidant signaling is one of the functions of the neuron-astrocyte tripartite synapse; by matching the astrocyte neuroprotective capacity to the degree of activity in adjacent neuronal synapses, this regulatory mechanism may limit the physiologic costs associated with Nrf2 activation.
红细胞生成素相关因子 2（Nrf2）是应激诱导抗氧化反应的转录主调控因子，在神经元抵抗氧化应激和谷氨酸诱导的兴奋性毒性方面发挥着关键作用。Nrf2 介导的神经保护作用主要是由体外和体内的星形胶质细胞赋予的，但对于调节神经元和星形胶质细胞 Nrf2 信号的生理信号知之甚少。在这里，我们报告说，通过神经元和星形胶质细胞之间的调节环，可以精细调节大脑中 Nrf2 途径的活性：升高的神经元活性导致谷氨酸和其他可溶性因子的分泌，通过涉及 I 组代谢型谷氨酸受体和细胞内 Ca(2+)的信号级联反应，激活星形胶质细胞 Nrf2 途径。因此，内源性抗氧化信号的调节是神经元-星形胶质细胞三突触的功能之一；通过使星形胶质细胞的神经保护能力与相邻神经元突触的活性程度相匹配，这种调节机制可能会限制与 Nrf2 激活相关的生理成本。
