Cardona Astrid E, Pioro Erik P, Sasse Margaret E, Kostenko Volodymyr, Cardona Sandra M, Dijkstra Ineke M, Huang Deren, Kidd Grahame, Dombrowski Stephen, Dutta RanJan, Lee Jar-Chi, Cook Donald N, Jung Steffen, Lira Sergio A, Littman Dan R, Ransohoff Richard M
Neuroinflammation Research Center and Department of Neurosciences, Lerner Research Institute, Cleveland, Ohio 44195, USA.
Nat Neurosci. 2006 Jul;9(7):917-24. doi: 10.1038/nn1715. Epub 2006 Jun 18.
Microglia, the resident inflammatory cells of the CNS, are the only CNS cells that express the fractalkine receptor (CX3CR1). Using three different in vivo models, we show that CX3CR1 deficiency dysregulates microglial responses, resulting in neurotoxicity. Following peripheral lipopolysaccharide injections, Cx3cr1-/- mice showed cell-autonomous microglial neurotoxicity. In a toxic model of Parkinson disease and a transgenic model of amyotrophic lateral sclerosis, Cx3cr1-/- mice showed more extensive neuronal cell loss than Cx3cr1+ littermate controls. Augmenting CX3CR1 signaling may protect against microglial neurotoxicity, whereas CNS penetration by pharmaceutical CX3CR1 antagonists could increase neuronal vulnerability.
小胶质细胞是中枢神经系统中的常驻炎性细胞，是唯一表达趋化因子受体（CX3CR1）的中枢神经系统细胞。我们使用三种不同的体内模型表明，CX3CR1缺陷会失调小胶质细胞反应，导致神经毒性。在外周注射脂多糖后，Cx3cr1-/-小鼠表现出细胞自主性小胶质细胞神经毒性。在帕金森病的毒性模型和肌萎缩侧索硬化症的转基因模型中，Cx3cr1-/-小鼠比Cx3cr1+同窝对照小鼠表现出更广泛的神经元细胞损失。增强CX3CR1信号传导可能预防小胶质细胞神经毒性，而药物性CX3CR1拮抗剂进入中枢神经系统可能会增加神经元的易损性。
