Center for Brain and Spinal Cord Repair, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA.
Exp Neurol. 2012 Jan;233(1):333-41. doi: 10.1016/j.expneurol.2011.10.025. Epub 2011 Nov 4.
It is widely believed that microglia and monocyte-derived macrophages (collectively referred to as central nervous system (CNS) macrophages) cause excitotoxicity in the diseased or injured CNS. This view has evolved mostly from in vitro studies showing that neurotoxic concentrations of glutamate are released from CNS macrophages stimulated with lipopolysaccharide (LPS), a potent inflammogen. We hypothesized that excitotoxic killing by CNS macrophages is more rigorously controlled in vivo, requiring both the activation of the glutamate/cystine antiporter (system x(c)(-)) and an increase in extracellular cystine, the substrate that drives glutamate release. Here, we show that non-traumatic microinjection of low-dose LPS into spinal cord gray matter activates CNS macrophages but without causing overt neuropathology. In contrast, neurotoxic inflammation occurs when LPS and cystine are co-injected. Simultaneous injection of NBQX, an antagonist of AMPA glutamate receptors, reduces the neurotoxic effects of LPS+cystine, implicating glutamate as a mediator of neuronal cell death in this model. Surprisingly, neither LPS nor LPS+cystine adversely affects survival of oligodendrocytes or oligodendrocyte progenitor cells. Ex vivo analyses show that redox balance in microglia and macrophages is controlled by induction of system x(c)(-) and that high GSH:GSSG ratios predict the neurotoxic potential of these cells. Together, these data indicate that modulation of redox balance in CNS macrophages, perhaps through regulating system x(c)(-), could be a novel approach for attenuating injurious neuroinflammatory cascades.
人们普遍认为，小胶质细胞和单核细胞衍生的巨噬细胞（统称为中枢神经系统（CNS）巨噬细胞）在患病或受伤的中枢神经系统中引起兴奋性毒性。这种观点主要来自于体外研究，表明脂多糖（LPS）刺激的中枢神经系统巨噬细胞释放出神经毒性浓度的谷氨酸，LPS 是一种有效的炎症原。我们假设，中枢神经系统巨噬细胞的兴奋性杀伤在体内受到更严格的控制，需要激活谷氨酸/胱氨酸反向转运体（system x(c)(-))并增加细胞外胱氨酸，后者是驱动谷氨酸释放的底物。在这里，我们表明，低剂量 LPS 非创伤性微注射到脊髓灰质中会激活中枢神经系统巨噬细胞，但不会引起明显的神经病理学。相比之下，当 LPS 和胱氨酸共同注射时，会发生神经毒性炎症。同时注射 NBQX，一种 AMPA 谷氨酸受体拮抗剂，可减轻 LPS+胱氨酸的神经毒性作用，表明谷氨酸是该模型中神经元细胞死亡的介质。令人惊讶的是，LPS 或 LPS+胱氨酸都不会对少突胶质细胞或少突胶质前体细胞的存活产生不利影响。离体分析表明，小胶质细胞和巨噬细胞中的氧化还原平衡受 system x(c)(-)的诱导控制，高 GSH:GSSG 比值预测这些细胞的神经毒性潜力。这些数据表明，调节中枢神经系统巨噬细胞的氧化还原平衡，也许通过调节 system x(c)(-)，可能是减轻有害神经炎症级联反应的一种新方法。
