Träger Ulrike, Andre Ralph, Magnusson-Lind Anna, Miller James R C, Connolly Colúm, Weiss Andreas, Grueninger Stephan, Silajdžić Edina, Smith Donna L, Leavitt Blair R, Bates Gillian P, Björkqvist Maria, Tabrizi Sarah J
UCL Institute of Neurology, Dept. of Neurodegenerative Disease, London, UK.
UCL Institute of Neurology, Dept. of Neurodegenerative Disease, London, UK; Wallenberg Neuroscience Centre, Dept. of Experimental Medical Science, Brain Disease Biomarker Unit, Lund University, Lund, Sweden.
Neurobiol Dis. 2015 Jan;73:388-98. doi: 10.1016/j.nbd.2014.10.012. Epub 2014 Oct 29.
Inflammation is a growing area of research in neurodegeneration. In Huntington's disease (HD), a fatal inherited neurodegenerative disease caused by a CAG-repeat expansion in the gene encoding huntingtin, patients have increased plasma levels of inflammatory cytokines and circulating monocytes that are hyper-responsive to immune stimuli. Several mouse models of HD also show elevated plasma levels of inflammatory cytokines. To further determine the degree to which these models recapitulate observations in HD patients, we evaluated various myeloid cell populations from different HD mouse models to determine whether they are similarly hyper-responsive, as well as measuring other aspects of myeloid cell function. Myeloid cells from each of the three mouse models studied, R6/2, HdhQ150 knock-in and YAC128, showed increased cytokine production when stimulated. However, bone marrow CD11b(+) cells did not show the same hyper-responsive phenotype as spleen and blood cells. Furthermore, macrophages isolated from R6/2 mice show increased levels of phagocytosis, similar to findings in HD patients. Taken together, these results show significant promise for these mouse models to be used to study targeting innate immune pathways identified in human cells, thereby helping to understand the role the peripheral immune system plays in HD progression.
炎症是神经退行性疾病研究中一个不断发展的领域。在亨廷顿舞蹈症（HD）中，这是一种由编码亨廷顿蛋白的基因中CAG重复序列扩增引起的致命遗传性神经退行性疾病，患者血浆中炎症细胞因子水平升高，循环单核细胞对免疫刺激反应过度。HD的几种小鼠模型也显示血浆炎症细胞因子水平升高。为了进一步确定这些模型在多大程度上重现了HD患者的观察结果，我们评估了来自不同HD小鼠模型的各种髓样细胞群体，以确定它们是否同样反应过度，并测量髓样细胞功能的其他方面。所研究的三种小鼠模型R6/2、HdhQ150基因敲入和YAC128中的每一种的髓样细胞在受到刺激时都显示出细胞因子产生增加。然而，骨髓CD11b(+)细胞没有表现出与脾脏和血细胞相同的反应过度表型。此外，从R6/2小鼠分离的巨噬细胞显示吞噬作用水平增加，这与HD患者的发现相似。综上所述，这些结果表明这些小鼠模型有望用于研究针对人类细胞中确定的先天性免疫途径，从而有助于了解外周免疫系统在HD进展中所起的作用。
