MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
BMC Neurosci. 2014 Mar 21;15:44. doi: 10.1186/1471-2202-15-44.
Microglia are resident mononuclear phagocytes of the brain that become activated in response to insults including neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and prion disease. In the central nervous system the chemokine Cx3cl1 (Fractalkine) is expressed by neurons and its exclusive receptor Cx3cr1 is expressed solely on microglia. Cx3cl1/Cx3cr1 signalling is thought to maintain microglia in their resting state and disrupting this equilibrium may allow microglia to become activated. In prion disease, microglial proliferation has been suggested to contribute to overall disease progression, however, in different mouse models of neurodegeneration, loss of Cx3cr1 has been shown to either worsen or improve the phenotype depending on the paradigm.
To investigate the role of Cx3cl1/Cx3cr1 signalling in prion disease we infected Cx3cr1 null mice with three different strains of prions. Following challenge with Chandler/RML, ME7 and MRC2 prion strains, Cx3cr1 knockout mice showed highly significant reductions in incubation time. No differences were seen in the pattern and localisation of activated microglia in the brain or in the mRNA expression levels of chemokines/cytokines (Cxcl10, Il-12b, Il-1b, Arg-1 and Cxc3l1).
Our data suggest a protective role for Cx3cl1/Cx3cr1 cross-talk in prion disease.
小胶质细胞是大脑中的固有单核吞噬细胞，在受到包括神经退行性疾病（如阿尔茨海默病、帕金森病和朊病毒病）等损伤时会被激活。在中枢神经系统中，趋化因子 Cx3cl1（ fractalkine）由神经元表达，其唯一的受体 Cx3cr1 仅在小胶质细胞上表达。Cx3cl1/Cx3cr1 信号被认为维持小胶质细胞处于静止状态，破坏这种平衡可能使小胶质细胞被激活。在朊病毒病中，小胶质细胞增殖被认为有助于疾病的总体进展，但在不同的神经退行性变小鼠模型中，Cx3cr1 的缺失显示出取决于范式的恶化或改善表型的作用。
为了研究 Cx3cl1/Cx3cr1 信号在朊病毒病中的作用，我们用三种不同的朊病毒株感染 Cx3cr1 敲除小鼠。在接受 Chandler/RML、ME7 和 MRC2 朊病毒株的挑战后，Cx3cr1 敲除小鼠的潜伏期显著缩短。在大脑中活化的小胶质细胞的模式和定位或趋化因子/细胞因子（Cxcl10、Il-12b、Il-1b、Arg-1 和 Cxc3l1）的 mRNA 表达水平上没有差异。
我们的数据表明 Cx3cl1/Cx3cr1 相互作用在朊病毒病中具有保护作用。
