The Center for Women Health Research, University of Wisconsin, Madison, WI, USA.
Neuroscience. 2011 Sep 8;190:67-74. doi: 10.1016/j.neuroscience.2011.06.006. Epub 2011 Jun 13.
Neuroinflammation mediated by microglia is a pathological hallmark of many CNS disorders. Cell lines derived from inbred C57Bl/6 and outbred ICR/CD1 mice (BV-2 and N9 respectively), are often used to study microglial inflammatory activities. Although many studies demonstrate different responses of these cell lines to the same stimulus, no comparisons have been done in vivo. Because inbreeding reduces resistance to pathogens and parasites, we hypothesized that microglia from outbred ICR/CD1 mice would have a stronger response to centrally administered LPS than microglia from inbred C57Bl/6 mice. The evaluation of gene expression in freshly isolated CD11b+ cells from brain revealed that microglia from ICR/CD1 mice were more pro-inflammatory than those from C57Bl/6 mice, although these differences did not appear to result from alterations in the expression levels of the LPS receptors TLR4 or CD14. Notably, the timing of inflammatory gene expression did not correlate with CD11b+ cell proliferation/infiltration. The highest expression of TNFα, IL-6 and iNOS occurred 3 h after LPS injection when the number of CD11b+ cells was not changed. Whereas the expression of these pro-inflammatory genes had returned to basal by 48 h when the highest number of CD11b+ cells in the brain was found, the expression of the anti-inflammatory cytokine IL-10 was still significantly up-regulated. This is important because the increased presence of CD11b+ cells in the CNS is often used as an indicator of neuroinflammation. While LPS did not affect the expression of the growth factors VEGF or BDNF, we observed that mechanical injury (caused by intraparenchymal injection) induced distinct patterns of microglial activation characterized by increased expression of VEGF and down-regulation of BDNF. It remains to be determined which type of microglia is more beneficial/detrimental to the CNS, but our data suggest that genetic traits determining microglial properties may have profound effect on many CNS pathologies.
小胶质细胞介导的神经炎症是许多中枢神经系统疾病的病理标志。源自近交系 C57Bl/6 和远交系 ICR/CD1 小鼠的细胞系（分别为 BV-2 和 N9）常用于研究小胶质细胞炎症活性。尽管许多研究表明这些细胞系对相同刺激的反应不同，但尚未在体内进行比较。由于近交降低了对病原体和寄生虫的抵抗力，我们假设来自远交系 ICR/CD1 小鼠的小胶质细胞对中枢给予 LPS 的反应会比来自近交系 C57Bl/6 小鼠的小胶质细胞更强。对来自大脑的新鲜分离的 CD11b+细胞中的基因表达进行评估表明，来自 ICR/CD1 小鼠的小胶质细胞比来自 C57Bl/6 小鼠的小胶质细胞更具炎症反应性，尽管这些差异似乎不是由于 LPS 受体 TLR4 或 CD14 的表达水平发生改变所致。值得注意的是，炎症基因表达的时间与 CD11b+细胞增殖/浸润无关。在 LPS 注射后 3 小时，TNFα、IL-6 和 iNOS 的表达最高，此时 CD11b+细胞数量没有变化。而当大脑中发现最多数量的 CD11b+细胞时，这些促炎基因的表达在 48 小时已恢复到基础水平，而抗炎细胞因子 IL-10 的表达仍显著上调。这很重要，因为中枢神经系统中 CD11b+细胞的增加通常被用作神经炎症的指标。虽然 LPS 不影响生长因子 VEGF 或 BDNF 的表达，但我们观察到，脑内注射引起的机械损伤导致小胶质细胞激活的独特模式，表现为 VEGF 表达增加和 BDNF 表达下调。尚需确定哪种类型的小胶质细胞对中枢神经系统更有益/有害，但我们的数据表明，决定小胶质细胞特性的遗传特征可能对许多中枢神经系统疾病产生深远影响。
