Krauthausen Marius, Saxe Simon, Zimmermann Julian, Emrich Michael, Heneka Michael T, Müller Marcus
Department of Neurology, Universitätsklinikum Bonn, Sigmund-Freud-Str, 25, D-53105 Bonn, Germany.
J Neuroinflammation. 2014 Jun 16;11:109. doi: 10.1186/1742-2094-11-109.
The functional state of glial cells, like astrocytes and microglia, critically modulates the course of neuroinflammatory and neurodegenerative diseases and can have both detrimental and beneficial effects. Glial cell function is tightly controlled by cellular interactions in which cytokines are important messengers. Recent studies provide evidence that in particular chemokines are important modulators of glial cell function. During the course of CNS diseases like multiple sclerosis or Alzheimer's disease, and in the corresponding animal models, the chemokines CXCL9 and CXCL10 are abundantly expressed at sites of glial activation, arguing for an important role of these chemokines and their corresponding receptor CXCR3 in glial activation. To clarify the role of this chemokine system in glial cell activation, we characterized the impact of CXCR3 on glial activation in a model of toxic demyelination in which glial activation without a prominent influx of hematogenous cells is prototypical.
We investigated the impact of CXCR3 on cuprizone-induced demyelination, comparing CXCR3-deficient mice with wild type controls. The clinical course during cuprizone feeding was documented for five weeks and for the subsequent four days withdrawal of the cuprizone diet (5.5 weeks). Glial activation was characterized using histological, histomorphometric and phenotypic analysis. Molecular analysis for (de)myelination and neuroinflammation was applied to characterize the effect of cuprizone on CXCR3-deficient mice and control animals.
CXCR3-deficient mice displayed a milder clinical course during cuprizone feeding and a more rapid body weight recovery after offset of diet. In the CNS, CXCR3 deficiency significantly attenuated the accumulation and activation of microglia and astrocytes. Moreover, a deficiency of CXCR3 reduced the expression of the microglial activation markers CD45 and CD11b. Compared to controls, we observed a vast reduction of RNA levels for proinflammatory cytokines and chemokines like Ccl2, Cxcl10, Tnf and Il6 within the CNS of cuprizone-treated mice. Lastly, CXCR3 deficiency had no major effects on the course of demyelination during cuprizone feeding.
The CXCR3 chemokine system is critically involved in the intrinsic glial activation during cuprizone-induced demyelination, which significantly modulates the distribution of glial cells and the local cytokine milieu.
神经胶质细胞（如星形胶质细胞和小胶质细胞）的功能状态对神经炎症性疾病和神经退行性疾病的进程具有关键调节作用，且可能产生有害和有益两种影响。神经胶质细胞的功能受到细胞间相互作用的严格控制，其中细胞因子是重要的信使。最近的研究表明，特别是趋化因子是神经胶质细胞功能的重要调节因子。在多发性硬化症或阿尔茨海默病等中枢神经系统疾病过程中，以及在相应的动物模型中，趋化因子CXCL9和CXCL10在神经胶质细胞激活部位大量表达，这表明这些趋化因子及其相应受体CXCR3在神经胶质细胞激活中起重要作用。为了阐明这种趋化因子系统在神经胶质细胞激活中的作用，我们在一种毒性脱髓鞘模型中研究了CXCR3对神经胶质细胞激活的影响，在该模型中，神经胶质细胞激活而无明显血源性细胞流入是典型特征。
我们研究了CXCR3对铜离子螯合剂诱导的脱髓鞘的影响，将CXCR3缺陷小鼠与野生型对照进行比较。记录了喂食铜离子螯合剂期间的临床病程，为期五周，随后在停止喂食铜离子螯合剂饮食后的四天（共5.5周）。使用组织学、组织形态计量学和表型分析来表征神经胶质细胞激活情况。应用脱髓鞘和神经炎症的分子分析来表征铜离子螯合剂对CXCR3缺陷小鼠和对照动物的影响。
CXCR3缺陷小鼠在喂食铜离子螯合剂期间临床病程较轻，停止饮食后体重恢复更快。在中枢神经系统中，CXCR3缺陷显著减弱了小胶质细胞和星形胶质细胞的积累和激活。此外，CXCR3缺陷降低了小胶质细胞激活标志物CD45和CD11b的表达。与对照相比，我们观察到在喂食铜离子螯合剂的小鼠中枢神经系统中，促炎细胞因子和趋化因子（如Ccl2、Cxcl10、Tnf和Il6）的RNA水平大幅降低。最后，CXCR3缺陷对喂食铜离子螯合剂期间的脱髓鞘病程没有重大影响。
CXCR3趋化因子系统在铜离子螯合剂诱导的脱髓鞘过程中对内在神经胶质细胞激活至关重要，这显著调节了神经胶质细胞的分布和局部细胞因子环境。
