Li Matthew D, Burns Terry C, Kumar Sunny, Morgan Alexander A, Sloan Steven A, Palmer Theo D
Department of Neurosurgery, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California.
Glia. 2015 May;63(5):754-67. doi: 10.1002/glia.22782. Epub 2015 Feb 17.
Whole brain irradiation remains important in the management of brain tumors. Although necessary for improving survival outcomes, cranial irradiation also results in cognitive decline in long-term survivors. A chronic inflammatory state characterized by microglial activation has been implicated in radiation-induced brain injury. We here provide the first comprehensive transcriptional profile of irradiated microglia. Fluorescence-activated cell sorting was used to isolate CD11b+ microglia from the hippocampi of C57BL/6 and Balb/c mice 1 month after 10 Gy cranial irradiation. Affymetrix gene expression profiles were evaluated using linear modeling and rank product analyses. One month after irradiation, a conserved irradiation signature across strains was identified, comprising 448 and 85 differentially up- and downregulated genes, respectively. Gene set enrichment analysis demonstrated enrichment for inflammation, including M1 macrophage-associated genes, but also an unexpected enrichment for extracellular matrix and blood coagulation-related gene sets, in contrast previously described microglial states. Weighted gene coexpression network analysis confirmed these findings and further revealed alterations in mitochondrial function. The RNA-seq transcriptome of microglia 24-h postradiation proved similar to the 1-month transcriptome, but additionally featured alterations in apoptotic and lysosomal gene expression. Reanalysis of published aging mouse microglia transcriptome data demonstrated striking similarity to the 1-month irradiated microglia transcriptome, suggesting that shared mechanisms may underlie aging and chronic irradiation-induced cognitive decline. GLIA 2015;63:754-767.
全脑照射在脑肿瘤的治疗中仍然很重要。尽管对于改善生存结果是必要的，但颅脑照射也会导致长期存活者出现认知功能下降。一种以小胶质细胞激活为特征的慢性炎症状态与辐射诱导的脑损伤有关。我们在此提供了受照射小胶质细胞的首个全面转录图谱。利用荧光激活细胞分选技术，从接受10 Gy颅脑照射1个月后的C57BL/6和Balb/c小鼠海马体中分离出CD11b+小胶质细胞。使用线性建模和秩乘积分析评估Affymetrix基因表达谱。照射后1个月，鉴定出一个跨品系的保守照射特征，分别包括448个和85个差异上调和下调基因。基因集富集分析表明炎症相关基因富集，包括M1巨噬细胞相关基因，但与先前描述的小胶质细胞状态相比，细胞外基质和血液凝固相关基因集也意外富集。加权基因共表达网络分析证实了这些发现，并进一步揭示了线粒体功能的改变。辐射后24小时小胶质细胞的RNA测序转录组与1个月时的转录组相似，但凋亡和溶酶体基因表达也有改变。对已发表的衰老小鼠小胶质细胞转录组数据的重新分析表明，其与1个月受照射小胶质细胞转录组有惊人的相似性，提示衰老和慢性照射诱导的认知功能下降可能存在共同机制。《胶质细胞》2015年；63:754 - 767。
